Organic compounds

ABSTRACT

The invention relates to particular prodrugs of substituted heterocycle fused gamma-carbolines, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving the 5-HT 2A  receptor, the serotonin transporter (SERT), pathways involving the dopamine D 1  and D 2  receptor signaling system, and/or the μ-opioid receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/537,292, filed on Jul. 26, 2017, and 62/647,492, filed on Mar. 23,2018; the contents of each of which are incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The invention relates to particular prodrugs of substituted heterocyclefused gamma-carbolines, in free, solid, pharmaceutically acceptable saltand/or substantially pure form as described herein, pharmaceuticalcompositions thereof, and methods of use in the treatment of diseasesinvolving the 5-HT_(2A) receptor, the serotonin transporter (SERT),pathways involving dopamine D₁ and/or D₂ receptor signaling systems,and/or the μ-opioid receptor, e.g., diseases or disorders such asanxiety, psychosis, schizophrenia, sleep disorders, sexual disorders,migraine, conditions associated with pain (including cephalic pain,neuropathic pain, and as an acute analgesic), fibromyalgia, chronicfatigue, social phobias, gastrointestinal disorders such as dysfunctionof the gastrointestinal tract motility and obesity; depression and mooddisorders, such as those associated with psychosis or Parkinson'sdisease; psychosis such as schizophrenia associated with depression;bipolar disorder; drug dependencies, such as opiate dependency andalcohol dependency, drug withdrawal symptoms; obsessive-compulsivedisorder (OCD), obsessive-compulsive personality disorder (OCPD), andrelated disorders; and other psychiatric and neurological conditions, aswell as to combinations with other agents. In some embodiments, thedisease or disorders may include treatment-resistant depression, cocainedependency, and/or amphetamine dependency, opioid use disorder and thesymptoms of opioid withdrawal.

BACKGROUND OF THE INVENTION

Substituted heterocycle fused gamma-carbolines are known to be agonistsor antagonists of 5-HT₂ receptors, particularly 5-HT_(2A) and 5-HT_(2C)receptors, in treating central nervous system disorders. These compoundshave been disclosed in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;6,713,471; 7,183,282; U.S. RE39680, and U.S. RE39679, as novel compoundsuseful for the treatment of disorders associated with 5-HT_(2A) receptormodulation such as obesity, anxiety, depression, psychosis,schizophrenia, sleep disorders, sexual disorders migraine, conditionsassociated with cephalic pain, social phobias, gastrointestinaldisorders such as dysfunction of the gastrointestinal tract motility,and obesity. PCT/US08/03340 (WO 2008/112280), and its U.S. equivalent US2010/113781 and U.S. application Ser. No. 10/786,935 (published as US2004/209864) also disclose methods of making substituted heterocyclefused gamma-carbolines and uses of these gamma-carbolines as serotoninagonists and antagonists useful for the control and prevention ofcentral nervous system disorders such as addictive behavior and sleepdisorders.

In addition, WO/2009/145900 (and its equivalent US 2011/071080)discloses use of particular substituted heterocycle fusedgamma-carbolines for the treatment of a combination of psychosis anddepressive disorders as well as sleep, depressive and/or mood disordersin patients with psychosis or Parkinson's disease. In addition todisorders associated with psychosis and/or depression, this patentapplication discloses and claims use of these compounds at a low dose toselectively antagonize 5-HT_(2A) receptors without affecting orminimally affecting dopamine D₂ receptors, thereby useful for thetreatment of sleep disorders without the side effects associated withhigh occupancy of the dopamine D₂ pathways or side effects of otherpathways (e.g., GABA_(A) receptors) associated with conventionalsedative-hypnotic agents (e.g., benzodiazepines) including but notlimited to the development of drug dependency, muscle hypotonia,weakness, headache, blurred vision, vertigo, nausea, vomiting,epigastric distress, diarrhea, joint pains, and chest pains. WO2009/114181 (and its equivalent US 2011/112105) also discloses ofmethods of preparing toluenesulfonic acid addition salt crystals ofthese substituted heterocycle fused gamma-carbolines.

In addition, recent evidence shows that the aforementioned substitutedfused heterocycle gamma carbolines may operate, in part, through NMDAreceptor antagonism via mTOR1 signaling, in a manner similar to that ofketamine. Ketamine is a selective NMDA receptor antagonist. Ketamineacts through a system that is unrelated to the common psychogenicmonoamines (serotonin, norepinephrine and dopamine), and this is a majorreason for its much more rapid effects. Ketamine directly antagonizesextrasynaptic glutamatergic NMDA receptors, which also indirectlyresults in activation of AMPA-type glutamate receptors. The downstreameffects involve the brain-derived neurotrophic factor (BDNF) and mTORC1kinase pathways. Similar to ketamine, recent evidence suggests thatcompounds related to those of the present disclosure enhance both NMDAand AMPA-induced currents in rat medial prefrontal cortex pyramidalneurons via activation of D1 receptors, and that this is associated withincreased mTORC1 signaling.

The related publications WO 2017/132408 and US 2017/319580 disclosenovel oxo-metabolites of the compounds disclosed in the above-mentionedpublications. These new oxo-metabolites retain much of the uniquepharmacologic activity of the parent compounds, including serotoninreceptor inhibition, SERT inhibition, and dopamine receptor modulation.However, these oxo-metabolites were found to unexpectedly also showsignificant activity at mu-opiate receptors.

Obsessive-compulsive disorder (OCD) and related disorders, have becomehighly prevalent and are difficult to treat. OCD is estimated to affectabout 2.3% of people at some point in their lives, and during a givenyear, it is estimated than 1.2% of people worldwide suffer from thedisorder. Half of people who suffer from OCD begin to show symptomsbefore the age of 20, which can seriously affect their ability to obtainan adequate and effective education. Without effective treatment,however, the disease can last for decades. The mainstay of pharmacologicOCD treatment is with selective serotonin reuptake inhibitors (SSRIs). Asecond line of therapy is with antipsychotic agents, such asclomipramine, risperidone, quetiapine and olanzapine. A significantnumber of patients either do not respond to these agents, or cannothandle the side effects caused by these agents. More recently, it hasbeen reported that the opioid analgesic tramadol may be effective intreating OCD. Opiates operate by an entirely different pathway fromtraditional OCD treatment agents, so they offer the possibility oftreatment for people who cannot take the traditional serotonergic agentsor for whom these agents are ineffective. However, strong opiate agentscan be addictive, and their use may be contraindicated in some patients.There thus remains an urgent need for new treatments for pain, OCD andother disorders.

Drug dependency disorders, such as opiate use disorder (OUD), areanother group of disorders which are difficult to successfully treat.Opioid overdoses claim approximately 100 lives in the United Statesevery day, and the opioid epidemic continues to grow in the UnitedStates. Methadone, buprenorphine, and naltrexone are the most frequentlyused treatments for OUD. Methadone is a mu-opioid receptor (MOP)agonist, buprenorphine is an MOP partial agonist, and naltrexone is anMOP antagonist. Each of these agents has had limited success, andlong-term adherence to prescribed therapies for OUD remains low. Inaddition, these treatments often exacerbate common co-morbiditiesassociated with OUD, such as mood and anxiety disorders, which furtherincreases the risk of remission. Abrupt opioid abuse withdrawal (i.e.,going “cold turkey”) is also associated with severe side effects,including dysphoria, depression and anxiety, and the common treatmentagents do not address these problems, and may make them worse. There isthus an urgent need for improved OUD treatments.

SUMMARY OF THE INVENTION

Compounds of Formula A and B, shown below, are potent serotonin5-HT_(2A) receptor antagonists and mu-opiate receptor partial agonistsor biased agonists. These compounds also interact with dopaminereceptors, particular the dopamine D1 receptors.

It is also believed that the Compounds of Formula A and/or B, via theirD1 receptor activity, may also enhance NMDA and AMPA mediated signalingthrough the mTOR pathway. The Compounds of Formula A and B and theiranalogs are useful for the treatment or prophylaxis of central nervoussystem disorders, but there is a need in the art for prodrugs of theCompounds of Formula A and B that when administered to a patient canprovide for improved therapeutic concentrations or improvedpharmacokinetic distribution or dynamics of these compounds. The presentdisclosure fills this need by providing Compounds of Formula I and II,et seq., which are prodrugs of the Compounds of Formula A and B, andtheir analogs. Due to their useful metabolic and pharmacokineticprofile, the Compounds of the present disclosure are particularly suitedfor formulation as long-acting or extended-release compositions thatwhen administered to a patient can provide for improved therapeuticamounts concentrations of the compounds A and B and their analogs overan extended period of time.

In a first aspect, the present disclosure relates to a compound(Compound I) of Formula I:

-   -   wherein:    -   R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)),        —C(O)—O—CH₂—O—C(R^(a))(R^(b))(R^(c)) or —C(R⁶)(R⁷)—O—C(O)—R⁸;    -   Z is O, or —C(O)—;    -   R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)), or        —N(R^(d))(R^(e));    -   R^(a), R^(b) and R^(c) are each independently selected from H        and C₁₋₂₄alkyl;    -   R^(d) and R^(e) are each independently selected from H and        C₁₋₂₄alkyl;    -   R⁶ and R⁷ are each independently selected from H, C₁₋₆alkyl,        carboxy and C₁₋₆alkoxycarbonyl;

in free or salt form (e.g., pharmaceutically acceptable salt form), forexample in an isolated or purified free or salt form (e.g.,pharmaceutically acceptable salt form).

The present disclosure provides additional exemplary embodiments of theCompound of Formula I, in free or salt form (e.g., pharmaceuticallyacceptable salt form), for example in an isolated or purified free orsalt form (e.g., pharmaceutically acceptable salt form), including:

-   -   1.1 Compound I, wherein Z is O;    -   1.2 Compound I, wherein Z is —C(O);    -   1.3 Compound I, 1.1, or 1.2, wherein R⁵ is        —C(O)—O—C(R^(a))(R^(b))(R^(c));    -   1.4 Compound 1.3, wherein R^(a) is H and R^(b) and R^(e) are        each independently selected from C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl,        C₅₋₂₀alkyl, C₉₋₁₈alkyl, C₁₀₋₁₆alkyl, or C₁₁alkyl, C₁₂alkyl,        C₁₃alkyl, C₁₄alkyl, C₁₅alkyl or C₁₆alkyl;    -   1.5 Compound 1.3, wherein R^(a) and R^(b) are H and R^(c) is        C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl, C₅₋₂₀alkyl, C₉₋₁₈alkyl,        C₁₀₋₁₆alkyl, or C₁₁alkyl, C₁₂alkyl, C₁₃alkyl, C₁₄alkyl, C₁₅alkyl        or C₁₆alkyl;    -   1.6 Compound 1.3, wherein R^(a), R^(b) and R^(c) are each        independently selected from C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl,        C₅₋₂₀alkyl, C₉₋₁₈alkyl, C₁₀₋₁₆alkyl, or C₁₁alkyl, C₁₂alkyl,        C₁₃alkyl, C₁₄alkyl, C₁₅alkyl or C₁₆alkyl;    -   1.7 Compound 1.3, wherein R^(a), R^(b) and R^(c) are each H;    -   1.8 Compound 1.3, wherein Z is O and R^(a) and R^(b) are H and        R^(c) is C₁₀₋₁₄alkyl (e.g., R^(c) is CH₃(CH₂)₁₀ or CH₃(CH₂)₁₄);    -   1.9 Compound I, 1.1, or 1.2, wherein R⁵ is        —C(O)—O—CH₂—O—C(R^(a))(R^(b))(R^(c));    -   1.10 Compound 1.9, wherein R^(a) is H and R^(b) and R^(c) are        each independently selected from C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl,        C₅₋₂₀alkyl, C₉₋₁₈alkyl, C₁₀₋₁₆alkyl, or C₁₁alkyl, C₁₂alkyl,        C₁₃alkyl, C₁₄alkyl, C₁₅alkyl or C₁₆alkyl;    -   1.11 Compound 1.9, wherein R^(a) and R^(b) are H and R^(c) is        C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl, C₅₋₂₀alkyl, C₉₋₁₈alkyl,        C₁₀₋₁₆alkyl, or C₁₁alkyl, C₁₂alkyl, C₁₃alkyl, C₁₄alkyl, C₁₈alkyl        or C₁₆alkyl;    -   1.12 Compound 1.9, wherein R^(a), R^(b) and R^(c) are each        independently selected from C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl,        C₅₋₂₀alkyl, C₉₋₁₈alkyl, C₁₀₋₁₆alkyl, or C₁₁alkyl, C₁₂alkyl,        C₁₃alkyl, C₁₄alkyl, C₁₈alkyl or C₁₆alkyl;    -   1.13 Compound 1.9, wherein R^(a), R^(b) and R^(c) are each H;    -   1.14 Compound I, 1.1, or 1.2, wherein R⁵ is        —C(R⁶)(R⁷)—O—C(O)—R⁸, and R⁸ is —C(R^(a))(R^(b))(R^(c));    -   1.15 Compound 1, 1.1, or 1.2, wherein R⁵ is        —C(R⁶)(R⁷)—O—C(O)—R⁸, and R⁸ is —O—C(R^(a))(R^(b))(R^(c));    -   1.16 Compound 1.14 or 1.15, wherein R^(a) is H and R^(b) and        R^(c) are each independently selected from C₁₋₂₄alkyl, e.g.,        C₁₋₂₀alkyl, C₅₋₂₀alkyl, C₉₋₁₈alkyl, C₁₀₋₁₆alkyl, or C₁₁alkyl,        C₁₂alkyl, C₁₃alkyl, C₁₄alkyl, C₁₅alkyl or C₁₆alkyl;    -   1.17 Compound 1.14 or 1.15, wherein R^(a) and R^(b) are H and        R^(c) is C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl, C₅₋₂₀alkyl, C₉₋₁₈alkyl,        C₁₀₋₁₆alkyl, or C₁₁alkyl, C₁₂alkyl, C₁₃alkyl, C₁₄alkyl, C₁₅alkyl        or C₁₆alkyl;    -   1.18 Compound 1.14 or 1.15, wherein R^(a), R^(b) and R^(c) are        each independently selected from C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl,        C₅₋₂₀alkyl, C₉₋₁₈alkyl, C₁₀₋₁₆alkyl, or C₁₆alkyl, C₁₂alkyl,        C₁₃alkyl, C₁₄alkyl, C₁₈alkyl or C₁₆alkyl;    -   1.19 Compound 1.14 or 1.15, wherein R^(a), R^(b) and R^(c) are        each H;    -   1.20 Compound 1.14, wherein Z is O and R⁶ is H, and R⁷ is        C₁₋₃alkyl (e.g., R⁷ is methyl or isopropyl), and R⁸ is        C₁₀₋₁₄alkyl (e.g., R⁸ is CH₃(CH₂)₁₀ or CH₃(CH₂)₁₄);    -   1.21 Compound I, 1.1, or 1.2, wherein R⁵ is        —C(R⁶)(R⁷)—O—C(O)—R⁸, and R⁸ is —N(R^(d))(R^(e));    -   1.22 Compound 1.21, wherein R^(d) is H and R^(e) is        independently selected from C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl,        C₅₋₂₀alkyl, C₉₋₁₈alkyl, C₁₀₋₁₆alkyl, or C₁₁alkyl, C₁₂alkyl,        C₁₃alkyl, C₁₄alkyl, C₁₈alkyl or C₁₆alkyl;    -   1.23 Compound 1.21, wherein R^(d) and R⁴ are each independently        selected from C₁₋₂₄alkyl, e.g., C₁₋₂₀alkyl, C₅₋₂₀alkyl,        C₉₋₁₈alkyl, C₁₀₋₁₆alkyl, or C₁₁alkyl, C₁₂alkyl, C₁₃alkyl,        C₁₄alkyl, C₁₅alkyl or C₁₆alkyl;    -   1.24 Compound 1.21, wherein R^(d) and R⁴ are each H;    -   1.25 Any of Compounds 1.14-1.24, wherein R⁶ is H and R⁷ is H;    -   1.26 Any of Compounds 1.14-1.24, wherein R⁶ is C₁₋₆alkyl and R⁷        is C₁₋₆alkyl;    -   1.27 Any of Compounds 1.14-1.24, wherein R⁶ is H and R⁷ is        C₁₋₆alkyl;    -   1.28 Any of Compounds 1.14-1.24, wherein R⁶ is H and R⁷ is        carboxy;    -   1.29 Any of Compounds 1.14-1.24, wherein R⁶ is H and R⁷ is        C₁₋₆alkoxycarbonyl, e.g., ethoxycarbonyl or methoxycarbonyl;    -   1.30 Compound I, or any of 1.1-1.29, in free form;    -   1.31 Compound I, or any of 1.1-1.29 in salt form, e.g.,        pharmaceutically acceptable salt form;    -   1.32 Compound I, or any of 1.1-1.31, in substantially pure        diastereomeric form (i.e., substantially free from other        diastereomers);    -   1.33 Compound I or any of 1.1-1.31, having a diastereomeric        excess of greater than 70%, preferably greater than 80%, more        preferably greater than 90% and most preferably greater than        95%.    -   1.34 Compound I or any of 1.1-1.33 in solid form.

in free or salt form (e.g., pharmaceutically acceptable salt form), forexample in an isolated or purified free or salt form (e.g.,pharmaceutically acceptable salt form).

In a second aspect, the present disclosure relates to a compound(Compound II) of Formula II:

-   -   wherein:    -   Z is O, or —C(O)—;    -   R¹, R², R³ and R⁴ are each independently selected from H and        C₁₋₆alkyl;    -   n is an integer from 1 to 23;

in free or salt form (e.g., pharmaceutically acceptable salt form), forexample in an isolated or purified free or salt form (e.g.,pharmaceutically acceptable salt form).

The present disclosure provides additional exemplary embodiments of theCompound of Formula II, in free or salt form (e.g., pharmaceuticallyacceptable salt form), for example in an isolated or purified free orsalt form (e.g., pharmaceutically acceptable salt form), including:

-   -   2.1 Compound II, wherein Z is O;    -   2.2 Compound II, wherein Z is —C(O);    -   2.3 Compound II, 2.1, or 2.2, wherein R¹ and R³ are H and R² and        R⁴ are each independently selected from C₁₋₆alkyl, e.g.,        C₁₋₄alkyl, C₁₋₃alkyl, or C₁₋₂alkyl;    -   2.4 Compound II, 2.1, or 2.2, wherein R¹ and R² are H and R³ and        R⁴ are each independently selected from C₁₋₆alkyl, e.g.,        C₁₄alkyl, C₁₋₃alkyl, or C₁₋₂alkyl;    -   2.5 Compound II, 2.1, or 2.2, wherein R¹, R², R³ and R⁴ are each        independently selected from C₁₋₆alkyl, e.g., C₁₋₄alkyl,        C₁₋₃alkyl, or C₁₋₂alkyl;    -   2.6 Compound II, 2.1, or 2.2, wherein R¹, R², R³ and R⁴ are each        H;    -   2.7 Compound II or any of compounds 2.1-2.6, wherein n is an        integer from 1-21, e.g., from 3-21 or from 3-15 or from 5-15 or        from 7-13 or from 7-11;    -   2.8 Compound II, or any of 2.1-2.7, in free form;    -   2.9 Compound II, or any of 2.1-2.7 in salt form, e.g.,        pharmaceutically acceptable salt form;    -   2.10 Compound II, or any of 2.1-2.7 in solid form.        -   in free or salt form (e.g., pharmaceutically acceptable salt            form), for example in an isolated or purified free or salt            form (e.g., pharmaceutically acceptable salt form).

In a third aspect, the present disclosure provides each of the foregoingCompound I or 1.1-1.34, Compound II or 2.1-2.10, (hereinaftercollectively “Compounds of Formulas I-II et seq.” or “compounds of thedisclosure”) in pharmaceutically acceptable salt form (e.g.,pharmaceutically acceptable salt form). The present disclosure providesadditional exemplary embodiments of the Compounds of Formulas I-II etseq., including:

-   -   5.1 Compounds of Formulas I-II et seq., wherein the salt is an        acid addition salt selected from hydrochloric, hydrobromic,        sulfuric, sulfamic, phosphoric, nitric, acetic, propionic,        succinic, glycolic, stearic, lactic, malic, tartaric, citric,        ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,        benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,        toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,        isethionic, and the like;    -   5.2 Compounds of Formulas I-II et seq., wherein the salt is        fumaric acid addition salt;    -   5.3 Compounds of Formulas I-II et seq., wherein the salt is        phosphoric acid addition salt;    -   5.4 Compounds of Formulas I-II et seq., wherein the salt is a        toluenesulfonic acid addition salt;    -   5.5 Any of 5.1-5.4 wherein the salt is in solid form.

In a fourth aspect, the present disclosure provides a pharmaceuticalcomposition (Pharmaceutical Composition 6) comprising a compoundaccording to any one of Compound I or 1.1-1.34, Compound II or 2.1-2.10,(collectively, Compounds of Formulas I-II et seq. or compounds of thedisclosure), e.g., in admixture with a pharmaceutically acceptablediluent or carrier. The present disclosure provides additional exemplaryembodiments of Pharmaceutical Composition 6, including:

-   -   6.1 Pharmaceutical Composition 6, comprising Compound I or any        of 1.1-1.34;    -   6.2 Pharmaceutical Composition 6, comprising Compound II or any        of 2.1-2.10;    -   6.3 Pharmaceutical Composition 6 or any of 6.1-6.2, wherein the        Compound of Formula I-II et seq. is in solid form;    -   6.4 Pharmaceutical Composition 6 or any of 6.1-6.3, wherein the        Compound of Formulas I-II et seq. is in pharmaceutically        acceptable salt form (e.g., pharmaceutically acceptable salt        form) as described in Compounds 5.1-5.5;    -   6.5 Pharmaceutical Composition 6 or any of 6.1-6.4, wherein the        Compound of Formulas I-II et seq. is in admixture with a        pharmaceutically acceptable diluent or carrier.

In a further embodiment, the Pharmaceutical Compositions of the presentdisclosure, are for a sustained or delayed release, e.g., depot,formulation. In one embodiment, the depot formulation (Depot Formulation6.6) is the Pharmaceutical Composition of any of 6.1-6.5, preferably infree or pharmaceutically acceptable salt form, and preferably inadmixture with a pharmaceutically acceptable diluent or carrier, e.g.,providing sustained or delayed release as an injectable depot.

In a particular embodiment, the Depot Formulation 6.6 comprises acompound according to any one of Compound I or 1.1-1.34, or Compound IIor 2.1-2.10, in free base or pharmaceutically acceptable salt form,optionally in crystal form, wherein the compound has been milled to, orthe compound crystallized to, microparticle or nanoparticle size, e.g.,particles or crystals having a volume-based particle size (e.g.,diameter or Dv50) of 0.5 to 100 microns, for example, for example, 5-30microns, 10-20 microns, 20-100 microns, 20-50 microns or 30-50 microns.Such particles or crystals may be combined with a suitablepharmaceutically acceptable diluent or carrier, for example water, toform a depot formulation for injection. For example, the depotformulation may be formulated for intramuscular or subcutaneousinjection with a dosage of drug suitable for 4 to 6 weeks of treatment.In some embodiments, the particles or crystals have a surface area of0.1 to 5 m²/g, for example, 0.5 to 3.3 m²/g or from 0.8 to 1.2 m²/g.

In another embodiment, the present disclosure provides PharmaceuticalComposition 6.7, which is Pharmaceutical Composition 6 or any of6.1-6.6, wherein the Compound of Formulas I-II et seq. is in a polymericmatrix. In one embodiment, the Compound of the present disclosure isdispersed or dissolved within the polymeric matrix. In a furtherembodiment, the polymeric matrix comprises standard polymers used indepot formulations such as polymers selected from a polyester of ahydroxyfatty acid and derivatives thereof, or a polymer of an alkylalpha-cyanoacrylate, a polyalkylene oxalate, a polyortho ester, apolycarbonate, a polyortho-carbonate, a polyamino acid, a hyaluronicacid ester, and mixtures thereof. In a further embodiment, the polymeris selected from a group consisting of polylactide, poly d,l-lactide,poly glycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymer. Inanother embodiment, the polymer is selected form poly(glycolic acid),poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing,poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone,polydioxanone, poly(ortho carbonates), poly(acetals), poly(lacticacid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone),polyanhydrides, and natural polymers including albumin, casein, andwaxes, such as, glycerol mono- and distearate, and the like. In apreferred embodiment, the polymeric matrix comprisespoly(d,l-lactide-co-glycolide).

The (Pharmaceutical) Compositions 6 and 6.1-6.7 are particularly usefulfor sustained or delayed release, wherein the Compound of the presentdisclosure is released upon degradation of the polymeric matrix. TheseCompositions may be formulated for controlled- and/or sustained-releaseof the Compounds of the present disclosure (e.g., as a depotcomposition) over a period of up to 180 days, e.g., from about 14 toabout 30 to about 180 days. For example, the polymeric matrix maydegrade and release the Compounds of the present disclosure over aperiod of about 30, about 60 or about 90 days. In another example, thepolymeric matrix may degrade and release the Compounds of the presentdisclosure over a period of about 120, or about 180 days.

In still another embodiment, the Pharmaceutical Compositions of thepresent disclosure, for example the depot composition of the presentdisclosure, e.g., Pharmaceutical Composition 6.6 or 6.7, is formulatedfor administration by injection.

In a fifth aspect, the present disclosure provides the Compounds ofFormulas I-II et seq. as hereinbefore described, in an osmoticcontrolled release oral delivery system (OROS), which is described in WO2000/35419 (US 2001/0036472) and EP 1 539 115 (U.S. Pub. No.2009/0202631), the contents of each of which applications areincorporated by reference in their entirety. Therefore in one embodimentof the seventh aspect, the present disclosure provides a pharmaceuticalcomposition or device comprising (a) a gelatin capsule containing aCompound of any of Formulae I-II et seq. in free or pharmaceuticallyacceptable salt form or a Pharmaceutical Composition of the Invention,as hereinbefore described; (b) a multilayer wall superposed on thegelatin capsule comprising, in outward order from the capsule: (i) abarrier layer, (ii) an expandable layer, and (iii) a semipermeablelayer; and (c) and orifice formed or formable through the wall(Pharmaceutical Composition P.1).

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a gelatin capsule containing a liquid, theCompound of Formulas I-II et seq. in free or pharmaceutically acceptablesalt form or a Pharmaceutical Composition of the Invention, e.g., any ofPharmaceutical Composition 6 or 6.1-6.7, the gelatin capsule beingsurrounded by a composite wall comprising a barrier layer contacting theexternal surface of the gelatin capsule, an expandable layer contactingthe barrier layer, a semi-permeable layer encompassing the expandablelayer, and an exit orifice formed or formable in the wall(Pharmaceutical Composition P.2).

In still another embodiment of the seventh aspect, the inventionprovides a composition comprising a gelatin capsule containing a liquid,the Compound of Formulas I-II et seq. in free or pharmaceuticallyacceptable salt form or a Pharmaceutical Composition of the Invention,e.g., any of Pharmaceutical Composition 6 or 6.1-6.7, the gelatincapsule being surrounded by a composite wall comprising a barrier layercontacting the external surface of the gelatin capsule, an expandablelayer contacting the barrier layer, a semipermeable layer encompassingthe expandable layer, and an exit orifice formed or formable in thewall, wherein the barrier layer forms a seal between the expandablelayer and the environment at the exit orifice (PharmaceuticalComposition P.3).

In still another embodiment of the seventh aspect, the inventionprovides a composition comprising a gelatin capsule containing a liquid,the Compound of Formulas I-II et seq. in free or pharmaceuticallyacceptable salt form or a Pharmaceutical Composition of the Invention,e.g., any of Pharmaceutical Composition 6 or 6.1-6.7, the gelatincapsule being surrounded by a barrier layer contacting the externalsurface of the gelatin capsule, an expandable layer contacting a portionof the barrier layer, a semi-permeable layer encompassing at least theexpandable layer, and an exit orifice formed or formable in the dosageform extending from the external surface of the gelatin capsule to theenvironment of use (Pharmaceutical Composition P.4). The expandablelayer may be formed in one or more discrete sections, such as forexample, two sections located on opposing sides or ends of the gelatincapsule.

In a particular embodiment of the seventh aspect, the Compound of thepresent disclosure in the Osmotic-controlled Release Oral DeliverySystem (i.e., in Composition P.1-P.4) is in a liquid formulation, whichformulation may be neat, liquid active agent, liquid active agent in asolution, suspension, emulsion or self-emulsifying composition or thelike.

Further information on Osmotic-controlled Release Oral Delivery Systemcomposition including characteristics of the gelatin capsule, barrierlayer, an expandable layer, a semi-permeable layer; and orifice may befound in WO 2000/35419 and US 2001/0036472, the contents of which areincorporated by reference in their entirety.

Other Osmotic-controlled Release Oral Delivery System for the Compoundof Formulas I-II et seq. or the Pharmaceutical Composition of thepresent disclosure may be found in EP 1 539 115 (U.S. Pub. No.2009/0202631), the contents of which are incorporated by reference intheir entirety. Therefore, in another embodiment of the seventh aspect,the invention provides a composition or device comprising (a) two ormore layers, said two or more layers comprising a first layer and asecond layer, said first layer comprises the Compound of Formulas I-IIet seq., in free or pharmaceutically acceptable salt form, or aPharmaceutical Composition as herein before described said second layercomprises a polymer; (b) an outer wall surrounding said two or morelayers; and (c) an orifice in said outer wall (PharmaceuticalComposition P.5).

Pharmaceutical Composition P.5 preferably utilizes a semi-permeablemembrane surrounding a three-layer-core: in these embodiments, the firstlayer is referred to as a first drug layer and contains low amounts ofdrug (e.g., the Compound of Formulas I-II et seq.) and an osmotic agentsuch as salt, the middle layer referred to as the second drug layercontains higher amounts of drug, excipients and no salt; and the thirdlayer referred to as the push layer contains osmotic agents and no drug(Pharmaceutical Composition P.6). At least one orifice is drilledthrough the membrane on the first drug layer end of the capsule-shapedtablet.

Pharmaceutical Composition P.5 or P.6 may comprise a membrane defining acompartment, the membrane surrounding an inner protective subcoat, atleast one exit orifice formed or formable therein and at least a portionof the membrane being semi-permeable; an expandable layer located withinthe compartment remote from the exit orifice and in fluid communicationwith the semi-permeable portion of the membrane; a first drug layerlocated adjacent the exit orifice; and a second drug layer locatedwithin the compartment between the first drug layer and the expandablelayer, the drug layers comprising the Compound of the Invention in freeor pharmaceutically acceptable salt thereof (Pharmaceutical CompositionP.7). Depending upon the relative viscosity of the first drug layer andsecond drug layer, different release profiles are obtained. It isimperative to identify the optimum viscosity for each layer. In thepresent invention, viscosity is modulated by addition of salt, sodiumchloride. The delivery profile from the core is dependent on the weight,formulation and thickness of each of the drug layers.

In a particular embodiment, the invention provides PharmaceuticalComposition P.7 wherein the first drug layer comprising salt and thesecond drug layer containing no salt. Pharmaceutical Composition P.5-P.7may optionally comprise a flow-promoting layer between the membrane andthe drug layers.

Pharmaceutical Compositions P.1-P.7 will generally be referred to asOsmotic-controlled Release Oral Delivery System Composition.

In a sixth aspect, the invention provides a method (Method 1) for thetreatment or prophylaxis of a central nervous system disorder,comprising administering to a patient in need thereof a Compound ofFormulas I-II et seq. or a Pharmaceutical Composition 6 or 6.1-6.7 orP.1-P.7, for example Method 1 wherein the compound or compositionadministered is:

-   -   1.1 Compound I or any of 1.1-1.34, in free or pharmaceutically        acceptable salt form;    -   1.2 Compound II or any of 2.1-2.10, in free or pharmaceutically        acceptable salt form;    -   1.3 The Compounds of Embodiment 5 or any of 5.1-5.5;    -   1.4 a Pharmaceutical Composition as described by any of        Pharmaceutical Compositions 6 and 6.1-6.7;    -   1.5 Depot Composition as described in Depot Composition 6.6 or        6.7;    -   1.6 Pharmaceutical Composition P.1-P.7;    -   1.7 Osmotic-controlled Release Oral Delivery System Composition        as hereinbefore described;

In a further embodiment of the sixth aspect, the present disclosureprovides Method 1 or any of Methods 1.1-1.7, wherein the method isfurther as described as follows:

-   -   1.8 Method 1 or any of Methods 1.1-1.7, wherein the central        nervous system disorder is a disorder selected from a group        consisting of obesity, anxiety (including general anxiety,        social anxiety, and panic disorders), depression (for example        refractory depression and MDD), psychosis (including psychosis        associated with dementia, such as hallucinations in advanced        Parkinson's disease or paranoid delusions), schizophrenia, sleep        disorders (particularly sleep disorders associated with        schizophrenia and other psychiatric and neurological diseases),        sexual disorders, migraine, pain and conditions associated with        pain, including cephalic pain, idiopathic pain, chronic pain        (such as moderate to moderately severe chronic pain, for example        in patients requiring 24 hour extend treatment for other        ailments), neuropathic pain, dental pain, fibromyalgia, chronic        fatigue, agoraphobia, social phobias, agitation in dementia        (e.g., agitation in Alzheimer's disease), agitation in autism        and related autistic disorders, gastrointestinal disorders such        as dysfunction of the gastrointestinal tract motility, and        dementia, for example dementia of Alzheimer's disease or of        Parkinson's disease; mood disorders; drug dependencies, for        example, opiate dependency and/or alcohol dependency, and        withdrawal from drug or alcohol dependency (e.g., opiate        dependency); opiate overdose; co-morbidities associated with        drug dependencies, such as depression, anxiety and psychosis;        binge eating disorder; and obsessive-compulsive disorder (OCD),        obsessive-compulsive personality disorder (OCPD) and related        disorders; or opiate use disorder (OUD);    -   1.9 Method 1 or any of Methods 1.1-1.8, wherein the central        nervous system disorder is a disorder involving serotonin        5-HT_(2A), dopamine D1 and/or D2 receptor system and/or        serotonin reuptake transporter (SERT) pathways as similarly        described in WO/2009/145900 and US 2011/071080, the contents of        which are herein incorporated by reference in their entirety;    -   1.10 Method 1 or any of Methods 1.1-1.9, wherein the central        nervous system disorder is a disorder involving the μ-opioid        receptor;    -   1.11 Method 1 or any of Methods 1.1-1.10, wherein the central        nervous system disorder is a disorder selected from the        following: (i) psychosis, e.g., schizophrenia, in a patient        suffering from depression; (2) depression in a patient suffering        from psychosis, e.g., schizophrenia; (3) mood disorders        associated with psychosis and/or drug dependencies, e.g.,        schizophrenia or Parkinson's disease; (4) sleep disorders        associated with psychosis, e.g., schizophrenia or Parkinson's        disease; and (5) substance addiction, substance use disorders        and/or substance-induced disorders, optionally wherein the        patient suffers from residual symptoms of anxiety or anxiety        disorder; and optionally wherein the depression is        treatment-resistant depression;    -   1.12 Method 1 or any of Methods 1.1-1.11, wherein the central        nervous system disorder is psychosis, e.g., schizophrenia and        said patient is a patient suffering from depression;    -   1.13 Method 1 or any of Methods 1.1-1.12, wherein said patient        is unable to tolerate the side effects of conventional        antipsychotic drugs, e.g., chlorpromazine, haloperidol,        droperidol, fluphenazine, loxapine, mesoridazine molindone,        perphenazine, pimozide, prochlorperazine promazine,        thioridazine, thiothixene, trifluoperazine, brexpiprazole,        cariprazine, asenapine, lurasidone, clozapine, aripiprazole,        olanzapine, quetiapine, risperidone and ziprasidone;    -   1.14 Method 1 or any of Methods 1.1-1.13, wherein said patient        is unable to tolerate the side effects of non-narcotic        analgesics and/or opiate and opioid drugs, or wherein the use of        opiate drugs are contraindicated in said patient, for example,        due to prior substance abuse or a high potential for substance        abuse, such as opiate and opioid drugs including, e.g.,        morphine, codeine, thebaine, oripavine, morphine dipropionate,        morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine,        hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl,        alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil,        remifentanil, octfentanil, sufentanil, carfentanyl, meperidine,        prodine, promedol, propoxyphene, dextropropoxyphene, methadone,        diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol,        nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol,        and anileridine, or any combinations thereof.    -   1.15 Method 1 or any of Methods 1.1-1.14, wherein said patient        is unable to tolerate the side effects of conventional        antipsychotic drugs, e.g., haloperidol, brexpiprazole,        cariprazine, asenapine, lurasidone, aripiprazole, clozapine,        olanzapine, quetiapine, risperidone, and ziprasidone;    -   1.16 Method 1 or any of Methods 1.1-1.15, wherein said disorder        is depression and said patient is a patient suffering from        psychosis, e.g., schizophrenia, or Parkinson's disease;    -   1.17 Method 1 or any of Methods 1.1-1.15, wherein said disorder        is sleep disorder and said patient is suffering from depression;    -   1.18 Method 1 or any of Methods 1.1-1.15, wherein said one or        more disorders is sleep disorder and said patient is suffering        from psychosis, e.g., schizophrenia;    -   1.19 Method 1 or any of Methods 1.1-1.15, wherein said one or        more disorders is sleep disorder and said patient is suffering        from Parkinson's disease;    -   1.20 Method 1 or any of Methods 1.1-1.15, wherein said one or        more disorders is sleep disorder and said patient is suffering        from depression and psychosis, e.g., schizophrenia, or        Parkinson's disease.    -   1.21 Method 1 or any of 1.1-1.20, wherein said patient is        suffering from a drug dependency disorder, optionally in        conjunction with any preceding disorders, for example, wherein        said patient suffers from opiate dependency, cocaine dependency,        amphetamine dependency, and/or alcohol dependency, or from        withdrawal from drug or alcohol dependency (e.g. opiate,        cocaine, or amphetamine dependency), and optionally wherein the        patient suffers from a co-morbidity, such as anxiety, depression        or psychosis, or residual symptoms of anxiety or anxiety        disorder and/or altered mood (e.g., depression); further        optionally wherein the patient suffers from an opiate overdose;    -   1.22 Any of the foregoing methods, wherein the effective amount        is 1 mg-1000 mg, for example 2.5 mg-50 mg, or for a long-acting        formulation, 25 mg-1500 mg, for example, 50 mg to 500 mg, or 250        mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg;    -   1.23 Any of the foregoing methods, wherein the effective amount        is 1 mg-100 mg per day, for example 2.5 mg-50 mg per day;    -   1.24 Any of the foregoing methods wherein a condition to be        treated is dyskinesia, e.g. in a patient receiving dopaminergic        medications, e.g., medications selected from levodopa and        levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B        inhibitors), dopamine agonists, and anticholinergics, e.g.,        levodopa;    -   1.25 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease.

Substance-use disorders and substance-induced disorders are the twocategories of substance-related disorders defined by the Fifth Editionof the DSM (the Diagnostic and Statistical Manual of Mental Disorders,DSM-V). A substance-use disorder is a pattern of symptoms resulting fromuse of a substance which the individual continues to take, despiteexperiencing problems as a result. A substance-induced disorder is adisorder induced by use if the substance. Substance-induced disordersinclude intoxication, withdrawal, substance induced mental disorders,including substance induced psychosis, substance induced bipolar andrelated disorders, substance induced depressive disorders, substanceinduced anxiety disorders, substance induced obsessive-compulsive andrelated disorders, substance induced sleep disorders, substance inducedsexual dysfunctions, substance induced delirium and substance inducedneurocognitive disorders.

The DSM-V includes criteria for classifying a substance use disorder asmild, moderate or severe. In some embodiments of the methods disclosedherein, the substance use disorder is selected from a mild substance usedisorder, a moderate substance use disorder or a severe substance usedisorder. In some embodiments, the substance use disorder is a mildsubstance use disorder. In some embodiments, the substance use disorderis a moderate substance use disorder. In some embodiments, the substanceuse disorder is a severe substance use disorder.

Anxiety and depression are highly prevalent co-morbid disorders inpatients undergoing treatment of substance use or substance abuse. Acommon treatment for substance abuse disorder is the combination of thepartial opioid agonist buprenorphine with the opioid antagonistnaloxone, but neither of these drugs has any significant effect onanxiety or depression, thus leading to the common result that a thirddrug, such as a benzodiazepine-class anxiolytic agent or an SSRIanti-depressant, must also be prescribed. This makes treatment regimensand patient compliance more difficult. In contrast, the Compounds of thepresent disclosure provide opiate antagonism along with serotoninantagonism and dopamine modulation. This may result in significantenhancement of treatment of patients with substance use or abusedisorder concomitant with anxiety and/or depression.

The compounds of the present disclosure may have anxiolytic propertiesameliorating the need for treatment of a patient with an anxiolyticagent where said patients suffers from co-morbid anxiety. Thus, in someembodiments, the present disclosure provides a method according toMethod 1, or any of Methods 1.1-1.25, wherein the central nervous systemdisorder is a substance addiction, substance use disorders and/orsubstance-induced disorders, or a substance abuse disorder, for example,in a patient suffering from symptoms of anxiety or who is diagnosed withanxiety as a co-morbid disorder, or as a residual disorder, wherein themethod does not comprise the further administration of an anxiolyticagent, such as a benzodiazepine. Benzodiazepines are GABA-modulatingcompounds, including those discussed with reference to Method 3.1 and3.2 below.

In another embodiment of the sixth aspect, the present disclosureprovides Method 1 or any of Methods 1.1-1.7, wherein the method isfurther as described as follows:

-   -   1.26 Method 1 or any of Methods 1.1-1.25, wherein the central        nervous system disorder is a disorder selected from        obsessive-compulsive disorder (OCD), obsessive-compulsive        personality disorder (OCPD), general anxiety disorder, social        anxiety disorder, panic disorder, agoraphobia, compulsive        gambling disorder, compulsive eating disorder, body dysmorphic        disorder, hypochondriasis, pathological grooming disorder,        kleptomania, pyromania, attention deficit-hyperactivity disorder        (ADHD), attention deficit disorder (ADD), impulse control        disorder, and related disorders, and combination thereof.    -   1.27 Method 1 or any one Method 1.1-1.25, wherein the central        nervous system disorder is selected from obsessive-compulsive        disorder (OCD), obsessive-compulsive personality disorder        (OCPD), social anxiety disorder, panic disorder, agoraphobia,        compulsive gambling disorder, compulsive eating disorder, body        dysmorphic disorder and impulse control disorder.    -   1.28 Method 1 or any one of Method 1.1-1.25, wherein the central        nervous system disorder is obsessive-compulsive disorder (OCD)        or obsessive-compulsive personality disorder (OCPD).    -   1.29 Any foregoing method, wherein said patient is not        responsive to or cannot tolerate the side effects from,        treatment with selective serotonin reuptake inhibitors (SSRIs),        such as citalopram, escitalopram, fluoxetine, fluvoxamine,        paroxetine, and sertraline.    -   1.30 Any foregoing method, wherein said patient is not        responsive to or cannot tolerate the side effects from,        treatment with serotonin-norepinephrine reuptake inhibitors        (SNRIs), such as venlafaxine, sibutranine, duloxetine,        atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran.    -   1.31 Any foregoing method, wherein said patient is not        responsive to or cannot tolerate the side effects from,        treatment with antipsychotic agents, such as clomipramine,        risperidone, quetiapine and olanzapine.    -   1.32 Method 1 or any of Method 1.1-1.25, wherein the central        nervous system disorder is a pain disorder, e.g., a condition        associated with pain, such as cephalic pain, idiopathic pain,        neuropathic pain, chronic pain (e.g., moderate to moderately        severe chronic pain, for example, in patients requiring 24-hour        extended treatment for other ailments), fibromyalgia, dental        pain, traumatic pain, or chronic fatigue.    -   1.33 Any foregoing method, wherein the patient is not responsive        to or cannot tolerate the side effects of non-narcotic        analgesics and/or opiate and opioid drugs, or wherein the use of        opiate drugs are contraindicated in said patient, for example,        due to prior substance abuse or a high potential for substance        abuse, such as opiate and opioid drugs including, e.g.,        morphine, codeine, thebaine, oripavine, morphine dipropionate,        morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine,        hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl,        alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil,        remifentanil, octfentanil, sufentanil, carfentanyl, meperidine,        prodine, promedol, propoxyphene, dextropropoxyphene, methadone,        diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol,        nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol,        and anileridine, or any combinations thereof;    -   1.34 Method I or any of Methods 1.1-1.33, wherein the central        nervous system disease or disorder is a drug dependency (for        example, opiate dependency (i.e., opioid use disorder), cocaine        dependency, amphetamine dependency, and/or alcohol dependency),        or withdrawal from drug or alcohol dependency (e.g., opiate,        cocaine, or amphetamine dependency), and wherein the patient        also suffers from a co-morbidity, such as anxiety, depression or        psychosis; optionally wherein the patient also suffers from an        opiate overdose;    -   1.35 Any of the foregoing methods, wherein the effective amount        is 1 mg-1000 mg, preferably 2.5 mg-50 mg, or for a long-acting        formulation, 25 mg-1500 mg, for example, 50 mg to 500 mg, or 250        mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg;    -   1.36 Any of the foregoing methods, wherein the effective amount        is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day.

In still another embodiment, the present disclosure provides any of theMethods 1 or 1.1-1.36 as hereinbefore described wherein the disorder isschizophrenia or sleep disorder. In some embodiments, said schizophreniais associated with depression.

In still another embodiment, the present disclosure provides any ofMethods 1.1-1.36, wherein the Depot Composition of the Invention (e.g.,Depot Composition of any of formulae 6.6-6.7), or (Pharmaceutical)Composition 6 or 6.1-6.7, or Pharmaceutical Composition P.1-P.7, isadministered for controlled- and/or sustained-release of the Compoundsof the Invention over a period of from about 14 days, about 30 to about180 days, preferably over the period of about 30, about 60 or about 90days. Controlled- and/or sustained-release is particularly useful forcircumventing premature discontinuation of therapy, particularly forantipsychotic drug therapy where non-compliance or non-adherence tomedication regimes is a common occurrence.

In still another embodiment, the invention provides any Method 1 or1.1-1.36 as hereinbefore described, wherein the Depot Composition of thepresent disclosure is administered for controlled- and/orsustained-release of the Compounds of the Invention over a period oftime.

In another embodiment of the sixth aspect, the invention provides Method1, or any of Methods 1.1-1.36, e.g., any method of treating pain,wherein the patient suffers from a gastrointestinal disorder and/or apulmonary disorder. Traditional opioid analgesics suffer from twodominant side effects: gastrointestinal disturbances (including nausea,vomiting and constipation) and respiratory depression. 90 to 95% ofpatients taking opioids for long-term pain treatment develop seriousconstipation, requiring the long-term use of laxatives and/or enemas.The stronger opioids such as morphine, oxycodone and hydromorphoneproduce more severe constipation than other opioids. Respiratorydepression is the most serious adverse effect of opioid treatment as itcreates a risk of death, especially when patients combine (intentionallyor inadvertently) prescribed opioid analgesics with other licit orillicit respiratory depressants (including alcohol). Patients in need ofpain treatment, especially chronic pain treatment, are therefore atparticular risk of adverse effects if they suffer from a pre-existinggastrointestinal or pulmonary disorder. Unlike traditional opioidanalgesics, the compounds of the present invention provide analgesicrelief without significant adverse gastrointestinal effects and withoutsignificant respiratory depression. Therefore, such compounds wouldprovide improved safety and efficacy for patients in need of paintreatment having these preexisting GI and pulmonary disorders. Infurther embodiments, a compound of the present invention may be combinedwith a traditional opiate agent to provide improved pain control with adose-sparing effect as to the traditional opiate agent (andconcomitantly reduced risk of adverse effects).

Thus, in particular embodiments, the present invention further provides:

-   -   1.37 Method 1 or any of 1.1-1.36, wherein the patient suffers        from a pre-existing or co-morbid gastrointestinal disorder        and/or pulmonary disorder;    -   1.38 Method 1.37, wherein the pre-existing or co-morbid disorder        is selected from the group consisting of irritable bowel        syndrome, pelvic floor disorder, diverticulitis, inflammatory        bowel disease, colon or colorectal cancer, celiac disease,        non-celiac gluten sensitivity, asthma, chronic obstructive        pulmonary disease (COPD), dyspnea, pneumonia, congestive heart        failure, interstitial lung disease, pneumothorax, bronchitis,        pulmonary embolism, and traumatic chest injury (e.g., broken        sternum or ribs, bruised intercostal muscles);    -   1.39 Method 1.37 or 1.38 wherein the central nervous system        disorder is a pain disorder, e.g., a condition associated with        pain, such as cephalic pain, idiopathic pain, neuropathic pain,        chronic pain (e.g., moderate to moderately severe chronic pain,        for example, in patients requiring 24-hour extended treatment        for other ailments), fibromyalgia, dental pain, traumatic pain,        or chronic fatigue;    -   1.40 Any of Method 1 or 1.1-1.39, wherein the central nervous        system disorder is opiate use disorder, opiate withdrawal or        opiate dependency, and wherein the method provides relief from        withdrawal-induced symptoms (e.g., gastrointestinal symptoms        such as diarrhea, anxiety, depression, pain, sleep disturbances,        or any combination thereof);    -   1.41 Any of Method 1 or 1.1-1.40, wherein the method further        comprises the concurrent administration of another opiate or        opioid agent, e.g., administered simultaneously, separately or        sequentially;    -   1.42 Method 1.41, wherein the additional opiate or opioid agent        is selected from the group consisting of morphine, codeine,        thebaine, oripavine, morphine dipropionate, morphine        dinicotinate, dihydrocodeine, buprenorphine, etorphine,        hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl,        alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil,        remifentanil, octfentanil, sufentanil, carfentanyl, meperidine,        prodine, promedol, propoxyphene, dextropropoxyphene, methadone,        diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol,        nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol,        and anileridine, or any combinations thereof;    -   1.43 Any of Method 1 or 1.1-1.42, wherein the method further        comprises the concurrent administration of a NMDA receptor        antagonist, e.g., administered simultaneously, separately or        sequentially;    -   1.44 Method 1.43, wherein the NMDA receptor antagonist is        selected from the group consisting of ketamine (e.g., S-ketamine        and/or R-ketamine), hydroxynorketamine, memantine,        dextromethorphan, dextroallorphan, dextrorphan, amantadine, and        agmatine, or any combination thereof;    -   1.45 Any of methods 1.37-1.44, wherein the compound is the        compound of Formula I, wherein Z is —O—.

In a seventh aspect, the invention provides a method (Method 2) for theprophylaxis or treatment of one or more sleep disorders comprisingadministering to a patient in need thereof a Compound of Formulas I-IIet seq. or a Pharmaceutical Composition 6 or 6.1-6.7 or P.1-P.7, (Method2) for example Method 2 wherein the compound or composition administeredis:

-   -   2.1 Compound I or 1.1-1.34, in free or pharmaceutically        acceptable salt form;    -   2.2 Compound II or 2.1-2.10, in free or pharmaceutically        acceptable salt form;    -   2.3 Compound 5 or 5.1-5.5;    -   2.4 a Pharmaceutical Composition as described by any of        Compositions 6 and 6.1-6.7;    -   2.5 Depot Composition as described in Depot Composition 6.6 or        6.7;    -   2.6 Pharmaceutical Composition P.1-P.7;    -   2.7 Osmotic-controlled Release Oral Delivery System Composition        as hereinbefore described;

In a further embodiment of the seventh aspect, the invention providesMethod 2, or 2.1-2.7, wherein the sleep disorder includes sleepmaintenance insomnia, frequent awakenings, and waking up feelingunrefreshed; for example:

-   -   2.8 Any of the foregoing methods, wherein the sleep disorder is        sleep maintenance insomnia;    -   2.9 Any of the foregoing methods, wherein the effective amount        is 1 mg-5 mg, preferably 2.5-5 mg, per day;    -   2.10 Any of the foregoing methods, wherein the effective amount        is 2.5 mg or 5 mg, per day;    -   2.11 Any of the foregoing methods wherein the sleep disorder is        in a patient suffering from or at risk of dyskinesia, e.g., a        patient receiving dopaminergic medications, e.g., selected from        levodopa and levodopa adjuncts (carbidopa, COMT inhibitors,        MAO-B inhibitors), dopamine agonists, and anticholinergics,        e.g., receiving levodopa;    -   2.12 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease.

In a further embodiment of the seventh aspect, the invention providesMethod 2, or any of 2.1-2.12, wherein the sleep disorder includes sleepmaintenance insomnia, frequent awakenings, and waking up feelingunrefreshed.

The Compounds of the present disclosure, the Pharmaceutical Compositionsof the present disclosure or the Depot Compositions of the presentdisclosure may be used in combination with a second therapeutic agent,particularly at lower dosages than when the individual agents are usedas a monotherapy so as to enhance the therapeutic activities of thecombined agents without causing the undesirable side effects commonlyoccur in conventional monotherapy. Therefore, the Compounds of thepresent disclosure may be simultaneously, sequentially, orcontemporaneously administered with other anti-depressant,anti-psychotic, other hypnotic agents, and/or agents use to treatParkinson's disease or mood disorders. In another example, side effectsmay be reduced or minimized by administering a Compound of the presentdisclosure in combination with one or more second therapeutic agents infree or salt form (e.g., pharmaceutically acceptable salt form), whereinthe dosages of (i) the second therapeutic agent(s) or (ii) both Compoundof the present disclosure and the second therapeutic agents, are lowerthan if the agents/compounds are administered as a monotherapy. In aparticular embodiment, the Compounds of the present disclosure areuseful to treat dyskinesia in a patient receiving dopaminergicmedications, e.g., selected from levodopa and levodopa adjuncts(carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, andanticholinergics, e.g., such as are used in the treatment of Parkinson'sdisease.

In some further embodiments of the present disclosure, thePharmaceutical Compositions of the present disclosure or the DepotCompositions of the present disclosure may be used in combination with asecond therapeutic agent, particularly at lower dosages than when theindividual agents are used as a monotherapy so as to enhance thetherapeutic activities of the combined agents without causing theundesirable side effects, wherein the second therapeutic agent is anopiate antagonist or inverse agonist (e.g., naloxone). The Compounds ofthe present disclosure may be simultaneously, sequentially, orcontemporaneously administered with such opiate antagonists or opiateinverse agonists.

Therefore, in an eighth aspect, the present disclosure provides Method1, or any of Methods 1.1-1.45, or Method 2 or any of 2.1-2.12, furthercomprising the administration of one or more therapeutic agents to thepatient, wherein the one or more therapeutic agents are selected fromcompounds that modulate GABA activity (e.g., enhances the activity andfacilitates GABA transmission), a GABA-B agonist, a 5-HT receptormodulator (e.g., a 5-HT_(1A) agonist, a 5-HT_(2A) antagonist, a5-HT_(2A) inverse agonist, etc.), a melatonin receptor agonist, an ionchannel modulator (e.g., blocker), a serotonin-2 receptorantagonist/reuptake inhibitor (e.g., a compound having both 5-HT₂antagonism and serotonin reuptake inhibition, i.e., SARIs), an orexinreceptor antagonist, an H3 agonist or antagonist, a noradrenergicagonist or antagonist, a galanin agonist, a CRH antagonist, human growthhormone, a growth hormone agonist, estrogen, an estrogen agonist, aneurokinin-1 drug, an anti-depressant, and opiate agonist and/or partialopiate agonist (such as a mu-, kappa- or delta-opiate receptor agonistor partial agonist), or opiate antagonist or inverse agonist (such asmu-, kappa- or delta-opiate receptor antagonist or inverse agonist),nociceptin agonist, and an antipsychotic agent, e.g., an atypicalantipsychotic agent, in free or pharmaceutically acceptable salt form(Method 1-A and 2-A respectively; collectively, “Method 3”). In furtherembodiments of the eighth aspect, the present disclosure provides Method1, or any of Methods 1.1-1.45, or Method 2 or any of 2.1-2.12, furthercomprising the administration to the patient of one or more therapeuticagents selected from the foregoing and further selected from agonists orpartial agonists or antagonists or inverse agonists of the mu-opiate,kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors. Infurther embodiments of the tenth aspect, the present disclosure alsoprovides Method 1, or any of Methods 1.1-45, or Method 2 or any of2.1-2.12, further comprising the administration to the patient of one ormore therapeutic agents selected from a serotonin HT₆ receptorantagonist, and an mGluR-2, -3 or -5 receptor agonist or antagonist(including both positive and negative modulators and partial agonists).

In a further embodiment of the eighth aspect, the invention providesMethod 3 (i.e., Method 1-A or 2-A), further comprising theadministration to the patient of one or more therapeutic agents, asfollows:

-   -   3.1 Method 1-A or 2-A, wherein the therapeutic agent(s) is        compounds that modulate GABA activity (e.g., enhances the        activity and facilitates GABA transmission);    -   3.2 Method 1-A or 2-A or 3.1, wherein the GABA compound is        selected from a group consisting of one or more of doxepin,        alprazolam, bromazepam, clobazam, clonazepam, clorazepate,        diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,        nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;    -   3.3 Method 1-A or 2-A, wherein the therapeutic agent is an        additional 5HT₂a receptor antagonist;    -   3.4 Method 1-A or 2-A or 3.3, wherein said additional 5HT₂a        receptor antagonist is selected from one or more of        pimavanserin, ketanserin, risperidone, eplivanserin,        volinanserin (Sanofi-Aventis, France), pruvanserin, MDL 100907        (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena        Pharmaceuticals, San Diego, Calif.), and AVE8488        (Sanofi-Aventis, France);    -   3.5 Method 1-A or 2-A, wherein the therapeutic agent is a        melatonin receptor agonist;    -   3.6 Method 1-A or 2-A or 3.5, wherein the melatonin receptor        agonist is selected from a group consisting of one or more of        melatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan),        VEC-162 (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase        II Discovery) and agomelatine;    -   3.7 Method 1-A or 2-A, wherein the therapeutic agent is an ion        channel blocker;    -   3.8 Method I-A or 2-A or 3.7, wherein said ion channel blocker        is one or more of lamotrigine, gabapentin and pregabalin.    -   3.9 Method 1-A or 2-A, wherein the therapeutic agent is an        orexin receptor antagonist;    -   3.10 Method 1-A or 2-A or 3.9, wherein the orexin receptor        antagonist is selected from a group consisting of orexin, a        1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868        (GlaxoSmithKline) and a benzamide derivative;    -   3.11 Method 1-A or 2-A, wherein the therapeutic agent is the        serotonin-2 receptor antagonist/reuptake inhibitor (SARI);    -   3.12 Method 1-A or 2-A or 3.11, wherein the serotonin-2 receptor        antagonist/reuptake inhibitor (SARI) is selected from a group        consisting of one or more Org 50081 (Organon—Netherlands),        ritanserin, nefazodone, serzone and trazodone;    -   3.13 Method 1-A or 2-A, wherein the therapeutic agent is the        5HTIa agonist;    -   3.14 Method 1-A or 2-A or 3.13, wherein the 5HTIa agonist is        selected from a group consisting of one or more of repinotan,        sarizotan, eptapirone, buspirone and MN-305 (MediciNova, San        Diego, Calif.);    -   3.15 Method 1-A or 2-A, wherein the therapeutic agent is the        neurokinin-1 drug;    -   3.16 Method 1-A or 2-A or 3.15, wherein the neurokinin-1 drug is        Casopitant (GlaxoSmithKline);    -   3.17 Method 1-A or 2-A, wherein the therapeutic agent is an        antipsychotic agent;    -   3.18 Method 1-A or 2-A or 3.17, wherein the antipsychotic agent        is selected from a group consisting of chlorpromazine,        haloperidol, droperidol, fluphenazine, loxapine, mesoridazine,        molindone, perphenazine, pimozide, prochlorperazine promazine,        thioridazine, thiothixene, trifluoperazine, brexpiprazole,        cariprazine, asenapine, lurasidone, clozapine, aripiprazole,        olanzapine, quetiapine, risperidone, ziprasidone and        paliperidone;    -   3.19 Method 1-A or 2-A, wherein the therapeutic agent is an        anti-depressant;    -   3.20 Method 1-A or 2-A or 3.19, wherein the anti-depressant is        selected from amitriptyline, amoxapine, bupropion, citalopram,        clomipramine, desipramine, doxepin, duloxetine, escitalopram,        fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,        mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine        sulfate, protriptyline, sertraline, tranylcypromine, trazodone,        trimipramine, and venlafaxine;    -   3.21 Method 1-A or 2-A, 3.17 or 3.18, wherein the antipsychotic        agent is an atypical antipsychotic agent;    -   3.22 Method 1-A or 2-A, or any of 3.17-3.21, wherein the        atypical antipsychotic agent is selected from a group consisting        of brexpiprazole, cariprazine, asenapine, lurasidone, clozapine,        aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone,        and paliperidone;    -   3.23 Method 1-A or 2-A, wherein the therapeutic agent is        selected from any of methods 3.1-3.22, e.g., selected from a        group consisting of modafinil, armodafinil, doxepin, alprazolam,        bromazepam, clobazam, clonazepam, clorazepate, diazepam,        flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,        oxazepam, temazepam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,        pimavanserin, ketanserin, risperidone, eplivanserin,        volinanserin (Sanofi-Aventis, France), pruvanserin, MDL 100907        (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena        Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis,        France), repinotan, sarizotan, eptapirone, buspirone, MN-305        (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM®,        Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals,        Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine,        lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea,        SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a        benzamide derivative, Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone, trazodone, Casopitant        (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,        citalopram, clomipramine, desipramine, doxepin, duloxetine,        escitalopram, fluoxetine, fluvoxamine, imipramine,        isocarboxazid, maprotiline, mirtazapine, nefazodone,        nortriptyline, paroxetine, phenelzine sulfate, protriptyline,        sertraline, tranylcypromine, trazodone, trimipramine,        venlafaxine, chlorpromazine, haloperidol, droperidol,        fluphenazine, loxapine, mesoridazine, molindone, perphenazine,        pimozide, prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, brexpiprazole, cariprazine, asenapine,        lurasidone, clozapine, aripiprazole, olanzapine, quetiapine,        risperidone, ziprasidone and paliperidone;    -   3.24 Method 1-A or 2-A wherein the therapeutic agent is an H3        agonist;    -   3.25 Method 1-A or 2-A, wherein the therapeutic agent is an H3        antagonist;    -   3.26 Method 1-A or 2-A, wherein the therapeutic agent is a        noradrenergic agonist or antagonist;    -   3.27 Method 1-A or 2-A, wherein the therapeutic agent is a        galanin agonist;    -   3.28 Method 1-A or 2-A, wherein the therapeutic agent is a CRH        antagonist;    -   3.29 Method 1-A or 2-A, wherein the therapeutic agent is a human        growth hormone;    -   3.30 Method 1-A or 2-A, wherein the therapeutic agent is a        growth hormone agonist;    -   3.31 Method 1-A or 2-A, wherein the therapeutic agent is        estrogen;    -   3.32 Method 1-A or 2-A, wherein the therapeutic agent is an        estrogen agonist;    -   3.33 Method 1-A or 2-A, wherein the therapeutic agent is a        neurokinin-1 drug;    -   3.34 Method 1-A or 2-A, wherein a therapeutic agent is combined        with compounds of Formula (I) and the therapeutic agent is an        anti-Parkinson agent such as L-dopa, co-careldopa, duodopa,        stalevo, Symmetrel, benztropine, biperiden, bromocriptine,        entacapone, pergolide, pramipexole, procyclidine, ropinirole,        selegiline and tolcapone;    -   3.35 Method 1-A or 2-A, wherein the therapeutic agent is an        opiate agonist or partial opiate agonist, for example, a        mu-agonist or partial agonist, or a kappa-agonist or partial        agonist, including mixed agonist/antagonists (e.g., an agent        with partial mu-agonist activity and kappa-antagonist activity);    -   3.36 Method 3.35, wherein the therapeutic agent is        buprenorphine, optionally, wherein said method does not include        co-treatment with an anxiolytic agent, e.g., a GABA compound or        benzodiazepine;    -   3.37 Method 1-A or 2-A, wherein compounds of Formula (I) may be        used to treat sleep disorders, depression, psychosis, or any        combinations thereof, in patients suffering from the listed        diseases and/or Parkinson's disease;    -   3.38 Method 1-A or 2-A, wherein the disorder is selected from at        least one or more of psychosis, e.g., schizophrenia, depression,        mood disorders, sleep disorders (e.g., sleep maintenance and/or        sleep onset) or any combination of disorders thereof;    -   3.39 Method 1-A or 2-A, wherein the therapeutic agent(s) is an        opiate receptor antagonist or inverse agonist, e.g., a full        opiate antagonist, for example, selected from naloxone,        naltrexone, nalmefene, methadone, nalorphine, levallorphan,        samidorphan, nalodeine, cyprodime, or norbinaltorphimine;    -   3.40 Any of the foregoing methods wherein the disorder is sleep        disorder;    -   3.41 Any of the foregoing methods, wherein the disorder is sleep        disorder associated with psychosis, e.g., schizophrenia or        Parkinson's disease; in free or pharmaceutically acceptable salt        form.

In a ninth aspect of the invention, the combination of a Compound of thepresent disclosure and one or more second therapeutic agents asdescribed in Methods 1-A, 2-A or any of Methods 3 or 3.1-3.41 may beadministered to the patient as a Pharmaceutical Composition or a depotComposition as hereinbefore described. The combination compositions caninclude mixtures of the combined drugs, as well as two or more separatecompositions of the drugs, which individual compositions can be, forexample, co-administered together to a patient.

In a particular embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprisesadministering to the patient in need thereof, a Compound of theInvention in combination with an atypical antipsychotic agent, e.g., acompound selected from brexpiprazole, cariprazine, asenapine,lurasidone, clozapine, aripiprazole, olanzapine, quetiapine,risperidone, ziprasidone, or paliperidone, in free or pharmaceuticallyacceptable salt form, for example wherein the dosage of the atypicalantipsychotic agent is reduced and/or side effects are reduced.

In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprisesadministering to the patient in need thereof, a Compound of theInvention in combination with an anti-depressant, e.g., amitriptyline,amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin,duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine,isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline,paroxetine, phenelzine sulfate, protriptyline, sertraline,tranylcypromine, trazodone, trimipramine, or venlafaxine, in free orpharmaceutically acceptable salt form. Alternatively, theanti-depressant may be used as an adjunct medication in addition to thecompound of the Invention.

In still another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprisesadministering to a patient in need thereof, a Compound of the Inventionin combination with a compound that modulates GABA activity, e.g., acompound selected from doxepin, alprazolam, bromazepam, clobazam,clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam,midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon,zopiclone, eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam or anycombinations thereof, in free or pharmaceutically acceptable salt form.In other embodiments, the methods disclosed herein do not furthercomprise administration of an GABA compound, a benzodiazepine or anyother anxiolytic agent.

In another preferred embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41comprises administering to a patient in need thereof, a Compound of theInvention in combination with doxepin in free or pharmaceuticallyacceptable salt form. Dosages of doxepin can vary in any range known toa person of ordinary skill in the art. In one example, a 10 mg dose ofdoxepin may be combined with any dosage of a compound of the Invention.

In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprisesadministering to a patient in need thereof, a Compound of the Inventionin combination (including as part of a daily dosage regimen) with anatypical stimulant, e.g., a modafinil, adrafinil, or armodafinil. Aregimen incorporating a Compound of the Invention with such drugspromotes more regular sleep, and avoids side effects such as psychosisor mania associated with higher levels of such drugs, e.g., in thetreatment of bipolar depression, cognition associated withschizophrenia, and excessive sleepiness and fatigue in conditions suchas Parkinson's disease and cancer.

In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprisesadministering to a patient in need thereof, a Compound of the Inventionin combination (including as part of a daily dosage regimen) with anopiate receptor antagonist or inverse agonist, e.g., a full opiateantagonist, for example, selected from naloxone, naltrexone, nalmefene,methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime,or norbinaltorphimine.

In some of the foregoing embodiments, each of the Compounds of FormulasI-II et seq.; Pharmaceutical Compositions 6 and 6.1-6.5; DepoCompositions 6.6 and 6.7; Compositions P.1-P.7; Methods 1 and 1.1-1.45;and Methods 2 and 2.1-2.12; the compound of the present disclosure issubstantially free of compound of the compound of Formula A and/orsubstantially free of the compound of Formula B.

In a tenth aspect, the invention provides use of a compound as describedin the following:

-   -   11.1 Compound I or 1.1-1.34, in free or pharmaceutically        acceptable salt form;    -   11.2 Compound II or 2.1-2.10, in free or pharmaceutically        acceptable salt form;    -   11.3 Compound 5 or 5.1-5.5;    -   11.4 Pharmaceutical Composition 6 and 6.1-6.7;    -   11.5 Pharmaceutical Composition P.1-P.7;    -   11.6 Osmotic-controlled Release Oral Delivery System Composition        as hereinbefore described;        (in the manufacture of a medicament) for the treatment or        prophylaxis of one or more disorders as disclosed hereinbefore,        e.g., in any of Method 1 or 1.1-1.45, any of Method 2 and        2.1-2.12, and Method 3 or 3.3-3.41, or any methods described in        the eleventh aspect of the invention.

In the eleventh aspect, the invention provides a pharmaceuticalcomposition as hereinbefore described, e.g.:

-   -   12.1 Pharmaceutical Composition 6 and 6.1-6.7;    -   12.2 Pharmaceutical Composition P.1-P.7;    -   12.3 Osmotic-controlled Release Oral Delivery System Composition        as hereinbefore described,

for use in the treatment or prophylaxis of one or more disorders asdisclosed hereinbefore, e.g., in any of Methods 1 and 1.1-1.33, Methods2 and 2.1-2.12, Methods I-A, II-A, 3 or 3.1-3.41 or any methodsdescribed in the ninth or tenth aspects of the invention.

DETAILED DESCRIPTION OF THE INVENTION

If not otherwise specified or clear from context, the following terms asused herein have the following meetings:

The compounds of the present disclosure have biologically labilefunctional groups positioned within the compounds such that naturalmetabolic activity will remove the labile functional groups, resultingin the Compound of Formula A and/or the Compound of Formula B. As such,administration of the compounds of the present disclosure to a patientin need thereof result in a both immediate and delayed release to thetissues of said person the Compound of Formula A and/or the Compound ofFormula B. It is expected that compounds of the present disclosure donot have significant pharmacologic activity in themselves, but willserve as a reservoir of the pharmacologically active compounds ofFormula A and/or Formula B. In this way, the compounds of the presentdisclosure are particularly suited to formulation as long-actinginjectable (LAI) or “Depot” pharmaceutical compositions. Without beingbound by theory, an injected “depot” comprising a compound of thepresent disclosure will gradually release into the body tissues saidcompound, in which tissues said compound will be gradually metabolizedto yield a compound of Formula A and/or compound of Formula B. Suchdepot formulations may be further adjusted by the selection ofappropriate components to control the rate of dissolution and release ofthe compounds of the present disclosure.

The Compounds of Formula A and B have been showed to have a variety ofuseful pharmaceutical properties, each of which is expected to be sharedby the compounds of the present disclosure. For example, the compound ofFormula A and B have potent 5-HT_(2A), D₁ and Mu opiate antagonism,along with moderate D₁, D₂ and SERT antagonism. Furthermore, it has beenunexpectedly found that such compounds may operate as “biased” Mu opiateligands. This means that when the compounds bind to Mu opiate receptors,they may operate as partial Mu agonists via G-protein coupled signaling,but as Mu antagonists via beta-arrestin signaling. This is in contrastto the traditional opiate agonists morphine and fentanyl, which tend tostrongly activate both G-protein signaling and beta-arrestin signaling.The activation of beta-arrestin signaling by such drugs is thought tomediate the gastrointestinal dysfunction and respiratory suppressiontypically mediated by opiate drugs. Compounds according to the presentinvention, in particular compounds according to Formula I, are thereforeexpected to result in pain amelioration with less severegastrointestinal and respiratory side effects than existing opiateanalgesics. This effect has been shown in pre-clinical studies and PhaseII and Phase III clinical trials of the biased Mu agonist oliceridine.Oliceridine has been shown to result in biased mu agonism via G-proteincoupled signaling with reduced beta-arresting signaling compared tomorphine, and this has been linked to its ability to produce analgesiawith reduced respiratory side effects compared to morphine. Furthermore,because these compounds antagonize the beta-arrestin pathway, they areexpected to be useful in treating opiate overdose, because they willinhibit the most severe opiate adverse effects while still providingpain relief. Furthermore, these compounds also have sleep maintenanceeffect due to their serotonergic activity. As many people suffering fromchronic pain have difficulty sleeping due to the pain, these compoundscan help such patients sleep through the night due to the synergisticeffects of serotonergic and opiate receptor activities.

Thus, in certain embodiments, the Compounds of the present disclosuremay be used in a method of treating opiate use disorder (OUD), opiateoverdose, or opiate withdrawal, either alone, or in conjunction with anopiate antagonist or inverse agonist (e.g., naloxone or naltrexone).Compounds of the present disclosure are expected to show a strongability to mitigate the dysphoria and psychiatric comorbiditiesassociated with drug withdrawal (e.g., mood and anxiety disorders, sleepdisturbances), and it also provides potent analgesia but without theadverse effects (e.g., GI effects and pulmonary depression) and abusepotential seen with other opioid treatments (e.g., oxycodone, methadoneor buprenorphine). The unique pharmacologic profile of these compoundsshould also mitigate the risks of adverse drug-drug interactions (e.g.,alcohol). These compounds are therefore particularly suited to treatopiate use disorder and the symptoms associated with opiate withdrawal.In addition, to the compounds' direct effect on mu receptor activity,the compounds' effect on serotonergic pathways results inanti-depressant, sleep maintenance, and anxiolytic effects. Becausedepression and anxiety are key factors leading susceptible patients toopioid use in the first place, the compounds of the present disclosurewould both reduce the symptoms of opiate withdrawal at the same timethat they reduce the psychiatric co-morbidities which promote opioiduse—a two-pronged strategy to reduce the risk of remission. The sleepmaintenance provided by these compounds would further improve thequality of life of patients undergoing OUD treatment.

“Alkyl” as used herein is a saturated or unsaturated hydrocarbon moiety,e.g., one to twenty-one carbon atoms in length, unless indicatedotherwise; any such alkyl may be linear or branched (e.g., n-butyl ortert-butyl), preferably linear, unless otherwise specified. For example,“C₁₋₂₁ alkyl” denotes alkyl having 1 to 21 carbon atoms. In oneembodiment, alkyl is optionally substituted with one or more hydroxy orC₁₋₂₂alkoxy (e.g., ethoxy) groups. In another embodiment, alkyl contains1 to 21 carbon atoms, preferably straight chain and optionally saturatedor unsaturated, for example in some embodiments wherein R₁ is an alkylchain containing 1 to 21 carbon atoms, preferably 6-15 carbon atoms,16-21 carbon atoms, e.g., so that together with the —C(O)— to which itattaches, e.g., when cleaved from the compound of Formula I, forms theresidue of a natural or unnatural, saturated or unsaturated fatty acid.

The term “pharmaceutically acceptable diluent or carrier” is intended tomean diluents and carriers that are useful in pharmaceuticalpreparations, and that are free of substances that are allergenic,pyrogenic or pathogenic, and that are known to potentially cause orpromote illness. Pharmaceutically acceptable diluents or carriers thusexclude bodily fluids such as example blood, urine, spinal fluid,saliva, and the like, as well as their constituent components such asblood cells and circulating proteins. Suitable pharmaceuticallyacceptable diluents and carriers can be found in any of severalwell-known treatises on pharmaceutical formulations, for exampleAnderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology,Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., ThePharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams &Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-SecondEdition (The Pharmaceutical Press, London, 1999); all of which areincorporated by reference herein in their entirety.

The terms “purified,” “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g., from a reaction mixture),or natural source or combination thereof. Thus, the term “purified,” “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization, LC-MS andLC-MS/MS techniques and the like), in sufficient purity to becharacterizable by standard analytical techniques described herein orwell known to the skilled artisan.

Unless otherwise indicated, the Compounds of the present disclosure,e.g., Compound I or 1.1-1.34, Compound II or 2.1-2.10 (collectively,Compounds of Formulas I-II et seq.) may exist in free or salt, e.g., asacid addition salts, form. An acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, acid acetic,trifluoroacetic, citric, maleic acid, toluene sulfonic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic acid, and the like. In addition, asalt of a compound of the invention which is sufficiently acidic is analkali metal salt, for example a sodium or potassium salt, an alkalineearth metal salt, for example a calcium or magnesium salt, an ammoniumsalt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)-amine. In a particular embodiment, the salt of theCompounds of the Invention is a toluenesulfonic acid addition salt. Inanother particular embodiment, the salt of the Compounds of theInvention is a fumaric acid addition salt. In a particular embodiment,the salt of the Compounds of the Invention is a phosphoric acid additionsalt.

The Compounds of the present disclosure are intended for use aspharmaceuticals, therefore pharmaceutically acceptable salts arepreferred. Salts which are unsuitable for pharmaceutical uses may beuseful, for example, for the isolation or purification of free Compoundsof the Invention, and are therefore also included within the scope ofthe compounds of the present disclosure.

The Compounds of the present disclosure may comprise one or more chiralcarbon atoms. The compounds thus exist in individual isomeric, e.g.,enantiomeric or diastereomeric form or as mixtures of individual forms,e.g., racemic/diastereomeric mixtures. Any isomer may be present inwhich the asymmetric center is in the (R)-, (S)-, or(R,S)-configuration. The invention is to be understood as embracing bothindividual optically active isomers as well as mixtures (e.g.,racemic/diastereomeric mixtures) thereof. Accordingly, the Compounds ofthe Invention may be a racemic mixture or it may be predominantly, e.g.,in pure, or substantially pure, isomeric form, e.g., greater than 70%enantiomeric/diastereomeric excess (“ee”), preferably greater than 80%ee, more preferably greater than 90% ee, most preferably greater than95% ee. The purification of said isomers and the separation of saidisomeric mixtures may be accomplished by standard techniques known inthe art (e.g., column chromatography, preparative TLC, preparative HPLC,simulated moving bed and the like).

Geometric isomers by nature of substituents about a double bond or aring may be present in cis (Z) or trans (E) form, and both isomericforms are encompassed within the scope of this invention.

It is also intended that the compounds of the present disclosureencompass their stable and unstable isotopes. Stable isotopes arenonradioactive isotopes which contain one additional neutron compared tothe abundant nuclides of the same species (i.e., element). It isexpected that the activity of compounds comprising such isotopes wouldbe retained, and such compound would also have utility for measuringpharmacokinetics of the non-isotopic analogs. For example, the hydrogenatom at a certain position on the compounds of the disclosure may bereplaced with deuterium (a stable isotope which is non-radioactive).Examples of known stable isotopes include, but not limited to,deuterium, ¹³C, ¹⁵N, ¹⁸O. Alternatively, unstable isotopes, which areradioactive isotopes which contain additional neutrons compared to theabundant nuclides of the same species (i.e., element), e.g., ¹²³I, ¹³¹I,¹²⁵I, ¹¹C, ¹⁸F, may replace the corresponding abundant species of I, Cand F. Another example of useful isotope of the compound of theinvention is the ¹¹C isotope. These radio isotopes are useful forradio-imaging and/or pharmacokinetic studies of the compounds of theinvention. In addition, the substitution of atoms of having the naturalisotopic distributing with heavier isotopes can result in desirablechange in pharmacokinetic rates when these substitutions are made atmetabolically liable sites. For example, the incorporation of deuterium(²H) in place of hydrogen can slow metabolic degradation when theposition of the hydrogen is a site of enzymatic or metabolic activity.

Compounds of the present disclosure may be included as a depotformulation, e.g., by dispersing, dissolving or encapsulating theCompounds of the Invention in a polymeric matrix as described in any ofComposition 6 and 6.1-6.7, such that the Compound is continuallyreleased as the polymer degrades over time. The release of the Compoundsof the Invention from the polymeric matrix provides for the controlled-and/or delayed- and/or sustained-release of the Compounds, e.g., fromthe pharmaceutical depot composition, into a subject, for example awarm-blooded animal such as man, to which the pharmaceutical depot isadministered. Thus, the pharmaceutical depot delivers the Compounds ofthe Invention to the subject at concentrations effective for treatmentof the particular disease or medical condition over a sustained periodof time, e.g., 14-180 days, preferably about 30, about 60 or about 90days.

Polymers useful for the polymeric matrix in the Composition of theInvention (e.g., Depot composition of the Invention) may include apolyester of a hydroxyfatty acid and derivatives thereof or other agentssuch as polylactic acid, polyglycolic acid, polycitric acid, polymalicacid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactone ringopening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyricacid-glycolic acid copolymer, polylactic acid-polyethyleneglycolcopolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymerof an alkyl alpha-cyanoacrylate (for example poly(butyl2-cyanoacrylate)), a polyalkylene oxalate (for example polytrimethyleneoxalate or polytetramethylene oxalate), a polyortho ester, apolycarbonate (for example polyethylene carbonate orpolyethylenepropylene carbonate), a polyortho-carbonate, a polyaminoacid (for example poly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamicacid or poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and thelike, and one or more of these polymers can be used.

If the polymers are copolymers, they may be any of random, block and/orgraft copolymers. When the above alpha-hydroxycarboxylic acids,hydroxydicarboxylic acids and hydroxytricarboxylic acids have opticalactivity in their molecules, any one of D-isomers, L-isomers and/orDL-isomers may be used. Among others, alpha-hydroxycarboxylic acidpolymer (preferably lactic acid-glycolic acid polymer), its ester,poly-alpha-cyanoacrylic acid esters, etc. may be used, and lacticacid-glycolic acid copolymer (also referred to aspoly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), andhereinafter referred to as PLGA) are preferred. Thus, in one aspect thepolymer useful for the polymeric matrix is PLGA. As used herein, theterm PLGA includes polymers of lactic acid (also referred to aspolylactide, poly(lactic acid), or PLA). Most preferably, the polymer isthe biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymeric matrix of the invention is abiocompatible and biodegradable polymeric material. The term“biocompatible” is defined as a polymeric material that is not toxic, isnot carcinogenic, and does not significantly induce inflammation in bodytissues. The matrix material should be biodegradable wherein thepolymeric material should degrade by bodily processes to productsreadily disposable by the body and should not accumulate in the body.The products of the biodegradation should also be biocompatible with thebody in that the polymeric matrix is biocompatible with the body.Particular useful examples of polymeric matrix materials includepoly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and natural polymersincluding albumin, casein, and waxes, such as, glycerol mono- anddistearate, and the like. The preferred polymer for use in the practiceof this invention is dl(polylactide-co-glycolide). It is preferred thatthe molar ratio of lactide to glycolide in such a copolymer be in therange of from about 75:25 to 50:50.

Useful PLGA polymers may have a weight-average molecular weight of fromabout 5,000 to 500,000 Daltons, preferably about 150,000 Daltons.Dependent on the rate of degradation to be achieved, different molecularweight of polymers may be used. For a diffusional mechanism of drugrelease, the polymer should remain intact until all of the drug isreleased from the polymeric matrix and then degrade. The drug can alsobe released from the polymeric matrix as the polymeric excipientbioerodes.

The PLGA may be prepared by any conventional method, or may becommercially available. For example, PLGA can be produced byring-opening polymerization with a suitable catalyst from cycliclactide, glycolide, etc. (see EP-0058481B2; Effects of polymerizationvariables on PLGA properties: molecular weight, composition and chainstructure).

It is believed that PLGA is biodegradable by means of the degradation ofthe entire solid polymer composition, due to the break-down ofhydrolysable and enzymatically cleavable ester linkages under biologicalconditions (for example in the presence of water and biological enzymesfound in tissues of warm-blooded animals such as humans) to form lacticacid and glycolic acid. Both lactic acid and glycolic acid arewater-soluble, non-toxic products of normal metabolism, which mayfurther biodegrade to form carbon dioxide and water. In other words,PLGA is believed to degrade by means of hydrolysis of its ester groupsin the presence of water, for example in the body of a warm-bloodedanimal such as man, to produce lactic acid and glycolic acid and createthe acidic microclimate. Lactic and glycolic acid are by-products ofvarious metabolic pathways in the body of a warm-blooded animal such asman under normal physiological conditions and therefore are welltolerated and produce minimal systemic toxicity.

In another embodiment, the polymeric matrix useful for the invention maycomprise a star polymer wherein the structure of the polyester isstar-shaped. These polyesters have a single polyol residue as a centralmoiety surrounded by acid residue chains. The polyol moiety may be, e.g., glucose or, e. g., mannitol. These esters are known and described inGB 2,145,422 and in U.S. Pat. No. 5,538,739, the contents of which areincorporated by reference.

The star polymers may be prepared using polyhydroxy compounds, e. g.,polyol, e.g., glucose or mannitol as the initiator. The polyol containsat least 3 hydroxy groups and has a molecular weight of up to about20,000 Daltons, with at least 1, preferably at least 2, e.g., as a mean3 of the hydroxy groups of the polyol being in the form of ester groups,which contain polylactide or co-polylactide chains. The branchedpolyesters, e.g., poly (d, l-lactide-co-glycolide) have a centralglucose moiety having rays of linear polylactide chains.

The depot compositions of the invention (e.g., Compositions 6 and6.1-6.10, in a polymer matrix) as hereinbefore described may comprisethe polymer in the form of microparticles or nanoparticles, or in aliquid form, with the Compounds of the Invention dispersed orencapsulated therein. “Microparticles” is meant solid particles thatcontain the Compounds of the Invention either in solution or in solidform wherein such compound is dispersed or dissolved within the polymerthat serves as the matrix of the particle. By an appropriate selectionof polymeric materials, a microparticle formulation can be made in whichthe resulting microparticles exhibit both diffusional release andbiodegradation release properties.

When the polymer is in the form of microparticles, the microparticlesmay be prepared using any appropriate method, such as by a solventevaporation or solvent extraction method. For example, in the solventevaporation method, the Compounds of the Invention and the polymer maybe dissolved in a volatile organic solvent (for example a ketone such asacetone, a halogenated hydrocarbon such as chloroform or methylenechloride, a halogenated aromatic hydrocarbon, a cyclic ether such asdioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile,or an alcohol such as ethanol) and dispersed in an aqueous phasecontaining a suitable emulsion stabilizer (for example polyvinylalcohol, PVA). The organic solvent is then evaporated to providemicroparticles with the Compounds of the Invention encapsulated therein.In the solvent extraction method, the Compounds of the Invention andpolymer may be dissolved in a polar solvent (such as acetonitrile,dichloromethane, methanol, ethyl acetate or methyl formate) and thendispersed in an aqueous phase (such as a water/PVA solution). Anemulsion is produced to provide microparticles with the Compounds of theInvention encapsulated therein. Spray drying is an alternativemanufacturing technique for preparing the microparticles.

Another method for preparing the microparticles of the invention is alsodescribed in both U.S. Pat. Nos. 4,389,330 and 4,530,840.

The microparticle of the present invention can be prepared by any methodcapable of producing microparticles in a size range acceptable for usein an injectable composition. One preferred method of preparation isthat described in U.S. Pat. No. 4,389,330. In this method the activeagent is dissolved or dispersed in an appropriate solvent. To theagent-containing medium is added the polymeric matrix material in anamount relative to the active ingredient that provides a product havingthe desired loading of active agent. Optionally, all of the ingredientsof the microparticle product can be blended in the solvent mediumtogether.

Solvents for the Compounds of the Invention and the polymeric matrixmaterial that can be employed in the practice of the present inventioninclude organic solvents, such as acetone; halogenated hydrocarbons,such as chloroform, methylene chloride, and the like; aromatichydrocarbon compounds; halogenated aromatic hydrocarbon compounds;cyclic ethers; alcohols, such as, benzyl alcohol; ethyl acetate; and thelike. In one embodiment, the solvent for use in the practice of thepresent invention may be a mixture of benzyl alcohol and ethyl acetate.Further information for the preparation of microparticles useful for theinvention can be found in U.S. Patent Publication Number 2008/0069885,the contents of which are incorporated herein by reference in theirentirety.

The amount of the Compounds of the present disclosure incorporated inthe microparticles usually ranges from about 1 wt % to about 90 wt. %,preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. By weight %is meant parts of the Compounds of the present disclosure per totalweight of microparticle.

The pharmaceutical depot compositions may comprise apharmaceutically-acceptable diluent or carrier, such as a water misciblediluent or carrier.

Details of Osmotic-controlled Release Oral Delivery System compositionmay be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631) and WO2000/35419 (US 2001/0036472), the contents of each of which areincorporated by reference in their entirety.

A “therapeutically effective amount” is any amount of the Compounds ofthe invention (for example as contained in the pharmaceutical depot)which, when administered to a subject suffering from a disease ordisorder, is effective to cause a reduction, remission, or regression ofthe disease or disorder over the period of time as intended for thetreatment.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular Compound of the Invention used, the mode ofadministration, and the therapy desired. Unless otherwise indicated, anamount of the Compound of the Invention for administration (whetheradministered as a free base or as a salt form) refers to or is based onthe amount of the Compound of the Invention in free base form (i.e., thecalculation of the amount is based on the free base amount).

Compounds of the Invention may be administered by any satisfactoryroute, including orally, parenterally (intravenously, intramuscular orsubcutaneous) or transdermally. In certain embodiments, the Compounds ofthe Invention, e.g., in depot formulation, is preferably administeredparenterally, e.g., by injection, for example, intramuscular orsubcutaneous injection.

In general, satisfactory results for Method 1 and 1.1-1.45, Method 2 and2.1-2.12, and Method 3 and 3.1-3.41, or use of the Compounds of thepresent disclosure as hereinbefore described, e.g. for the treatment ofa combination of diseases such as a combination of at least depression,psychosis, e.g., (1) psychosis, e.g., schizophrenia, in a patientsuffering from depression; (2) depression in a patient suffering frompsychosis, e.g., schizophrenia; (3) mood disorders associated withpsychosis, e.g., schizophrenia, or Parkinson's disease; (4) sleepdisorders associated with psychosis, e.g., schizophrenia, or Parkinson'sdisease; and (5) substance addiction, substance use disorders and/orsubstance-induced disorders, as set forth above are indicated to beobtained on oral administration at dosages of the order from about 1 mgto 100 mg once daily, preferably 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10mg, 20 mg, 30 mg, 40 mg or 50 mg, once daily, preferably via oraladministration.

Satisfactory results for Method 2 or 2.1-2.12 or use of the Compounds ofthe present disclosure as hereinbefore described, e.g. for the treatmentof sleep disorder alone are indicated to be obtained on oraladministration at dosages of the order from about 2.5 mg-5 mg, e.g., 2.5mg, 3 mg, 4 mg or 5 mg, of a Compound of the Invention, in free orpharmaceutically acceptable salt form, once daily, preferably via oraladministration.

Satisfactory results for Method 1-A or Method 2-A, or any of 3.1-3.41are indicated to be obtained at less than 100 mg, preferably less than50 mg, e.g., less than 40 mg, less than 30 mg, less than 20 mg, lessthan 10 mg, less than 5 mg, less than 2.5 mg, once daily. Satisfactoryresults for Method 11-A or any of 3.1-3.41 are indicated to be obtainedat less than 5 mg, preferably less than 2.5 mg.

For treatment of the disorders disclosed herein wherein the depotcomposition is used to achieve longer duration of action, the dosageswill be higher relative to the shorter action composition, e.g., higherthan 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greaterthan 1000 mg. Duration of action of the Compounds of the presentdisclosure may be controlled by manipulation of the polymer composition,i.e., the polymer:drug ratio and microparticle size. Wherein thecomposition of the invention is a depot composition, administration byinjection is preferred.

The pharmaceutically acceptable salts of the Compounds of the presentdisclosure can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free base forms of these compoundswith a stoichiometric amount of the appropriate acid in water or in anorganic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Further details for the preparation of these salts, e.g.,toluenesulfonic salt in amorphous or crystal form, may be found inPCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069 (eachequivalent to US 2011/112105).

Pharmaceutical compositions comprising Compounds of the presentdisclosure may be prepared using conventional diluents or excipients (anexample include, but is not limited to sesame oil) and techniques knownin the galenic art. Thus, oral dosage forms may include tablets,capsules, solutions, suspensions and the like.

The term “concurrently” when referring to a therapeutic use meansadministration of two or more active ingredients to a patient as part ofa regimen for the treatment of a disease or disorder, whether the two ormore active agents are given at the same or different times or whethergiven by the same or different routes of administrations. Concurrentadministration of the two or more active ingredients may be at differenttimes on the same day, or on different dates or at differentfrequencies.

The term “simultaneously” when referring to a therapeutic use meansadministration of two or more active ingredients at or about the sametime by the same route of administration.

The term “separately” when referring to a therapeutic use meansadministration of two or more active ingredients at or about the sametime by different route of administration

Methods of Making the Compounds of the Invention:

The Compound of Formula A, and methods for its synthesis, have beendisclosed in International Application PCT/US2017/15178, publishing asWO 2017/132408 and in US 2017/319580. The Compounds of the presentdisclosure, wherein Z is —O—, may be prepared, for example, by reactingthe Compound of Formula A with a suitable alkylating and acylatingagents, as appropriate, in accordance with Scheme 1 below. Other methodsfor carrying out similar transformations are known to those skilled inthe art.

Other Compounds of the present disclosure came be made by analogousprocedures known to those skilled in the art.

Isolation or purification of the diastereomers of the Compounds of theInvention may be achieved by conventional methods known in the art,e.g., column purification, preparative thin layer chromatography,preparative HPLC, crystallization, trituration, simulated moving bedsand the like.

Salts of the Compounds of the present disclosure may be prepared assimilarly described in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;6,713,471; 7,183,282; U.S. RE39680; U.S. RE39679; and WO 2009/114181 (US2011/112105), the contents of each of which are incorporated byreference in their entirety.

Diastereomers of prepared compounds can be separated by, for example,HPLC using CHIRALPAK® AY-H, 5μ, 30×250 mm at room temperature and elutedwith 10% ethanol/90% hexane/0.1% dimethylethylamine. Peaks can bedetected at 230 nm to produce 98-99.9% ee of the diastereomer.

Example 1: Synthesis of4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one

(6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylicacid ethyl ester (6.4 g, 21.2 mmol) is suspended in HBr acetic acidsolution (64 mL, 33% w/w) at room temperature. The mixture is heated at50° C. for 16 h. After cooling, and treatment with ethyl acetate (300mL), the mixture is filtered. The filter cake is washed with ethylacetate (300 mL), and then dried under vacuum. The obtained HBr salt isthen suspended in methanol (200 mL), and cooled with dry ice inisopropanol. Under vigorous stirring, ammonia solution (10 mL, 7N inmethanol) is added slowly to the suspension to adjust the pH of themixture to 10. The obtained mixture is dried under vacuum withoutfurther purification to give crude (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline(8.0 g), which is used directly in the next step. MS (ESI) m/z 230.2[M+H]⁺.

The crude (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline(1.4 g) is dissolved in DMF (14 mL), and then KI (2.15 g) and4-Chloro-4′-fluorobutyrophenone (2 mL) are added successively. Themixture is degassed with argon, followed by addingN,N-diisopropylethylamine (DIPEA, 2 mL). The mixture is heated at 78° C.for 2 h. After cooling, the solvents are removed under reduced pressure.The dark brown residue is suspended in dichloromethane (100 mL) and thenextracted with water (30 mL). The organic layer is separated, and driedover K₂CO₃. After filtration, the solvents are removed under reducedpressure. The obtained crude product is purified by silica gel columnchromatography eluting with 0-10% of methanol in ethyl acetatecontaining 0.1% of 7N ammonia in methanol to yield4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-oneas a light yellow solid (767 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.3 (s,1H), 8.1-8.0 (m, 2H), 7.3 (dd, J=8.86 Hz, 2H), 6.8 (d, J=7.25 Hz, 1H),6.6 (dd, J=7.55 Hz, 1H), 6.6 (d, J=7.74 Hz, 1H), 3.8 (d, J=14.49 Hz,1H), 3.3-3.3 (m, 1H), 3.2-3.2 (m, 1H), 3.1-3.0 (m, 1H), 3.0 (t, J=6.88Hz, 2H), 2.8-2.8 (m, 1H), 2.6-2.5 (m, 1H), 2.3-2.2 (m, 2H), 2.1-2.0 (m,1H), 1.9-1.8 (m, 1H), 1.8 (t, J=6.99 Hz, 2H), 1.6 (t, J=11.25 Hz, 2H).MS (ESI) m/z 394.2 [M+H]⁺.

Example 2: Synthesis of(6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

A mixture of(6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one(100 mg, 0.436 mmol), 1-(3-chloroproxy)-4-fluorobenzene (100 μL, 0.65mmol) and KI (144 mg, 0.87 mmol) in DMF (2 mL) is degassed with argonfor 3 minutes and DIPEA (150 μL, 0.87 mmol) is added. The resultingmixture is heated to 78° C. and stirred at this temperature for 2 h. Themixture is cooled to room temperature and then filtered. The filter cakeis purified by silica gel column chromatography using a gradient of0-100% ethyl acetate in a mixture of methanol/7N NH₃ in methanol (1:0.1v/v) as an eluent to produce partially purified product, which isfurther purified with a semi-preparative HPLC system using a gradient of0-60% acetonitrile in water containing 0.1% formic acid over 16 min toobtain the title product as a solid (50 mg, yield 30%). MS (ESI) m/z406.2 [M+1]+. ¹H NMR (500 MHz, DMSO-d₆) δ 10.3 (s, 1H), 7.2-7.1 (m, 2H),7.0-6.9 (m, 2H), 6.8 (dd, J=1.03, 7.25 Hz, 1H), 6.6 (t, J=7.55 Hz, 1H),6.6 (dd, J=1.07, 7.79 Hz, 1H), 4.0 (t, J=6.35 Hz, 2H), 3.8 (d, J=14.74Hz, 1H), 3.3-3.2 (m, 3H), 2.9 (dd, J=6.35, 11.13 Hz, 1H), 2.7-2.6 (m,1H), 2.5-2.3 (m, 2H), 2.1 (t, J=11.66 Hz, 1H), 2.0 (d, J=14.50 Hz, 1H),1.9-1.8 (m, 3H), 1.7 (t, J=11.04 Hz, 1H).

Example 3: Cellular and Nuclear Receptor Functional Assays

Cellular and Nuclear Receptor Functional Assays are performed on thecompound of Example 1 according to the procedure of Wang, J. B. et al.(1994), FEBS Lett., 338:217-222. The compound is tested at severalconcentrations to determine IC₅₀ or EC₅₀. Cellular agonist effects arecalculated as percent of control response to a known reference agonistfor each target and cellular antagonist effect is calculated as apercent inhibition of control reference agonist response for eachtarget.

The following assay is performed to determine the effect of the Compoundof Example 1 on the μ (MOP) (h) receptor:

Assay Measured Detection (Receptor) Source Stimulus Incubatio

Component Method μ (MOP) (h) human none 10 min @ cAMP HTRF (agonisteffect) recombinant (0.3 μM 37° C. MOP recepto

DAMGO (CHO cells) for control

μ (MOP) (h) human DAMGO 10 min @ cAMP HTRF (antagonist effec

recombinant (20 nM) 37° C. MOP recepto

(CHO cells)

indicates data missing or illegible when filed

For the antagonists, the apparent dissociation constants (K_(B)) arecalculated using the modified Cheng Prusoff equation:

$K_{B} = \frac{{IC}_{50}}{1 + ( {A/{EC}_{50A}} )}$

where A=concentration of reference agonist in the assay, andEC_(50A)=EC₅₀ value of the reference agonist.

The compound of Example 1 is found to have a p (MOP) (h) (antagonisteffect) with an IC₅₀ of 1.3×10⁻⁶M; and a K_(B) of 1.4×10⁻⁷M.

The agonist activity results are expressed as a percent of controlagonist response:

$\frac{{measured}{response}}{{control}{response}} \times 100$

and antagonist activity as a percent inhibition of control agonistmaximum response:

$100 - ( {\frac{{measured}{response}}{{control}{response}} \times 100} )$

obtained in the presence of the Compound of Example 1.

The EC₅₀ values (concentration producing a half-maximal response) andIC₅₀ values (concentration causing a half-maximal inhibition of thecontrol agonist response) are determined by non-linear regressionanalysis of the concentration-response curves generated with meanreplicate values using Hill equation curve fitting:

$Y = {D + \lbrack \frac{A - D}{1 + ( {C/C_{50}} )^{nH}} \rbrack}$

where Y=response, A=left asymptote of the curve, D=right asymptote ofthe curve, C=compound concentration, and C₅₀=EC₅₀ or IC₅₀, and nH=slopefactor. The analysis is performed using software developed in-house andvalidated by comparison with data generated by the commercial softwareSigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc.).

Example 4: Receptor Binding Profile

Receptor binding is determined for the Compounds of Example 1 and 2. Thefollowing literature procedures are used, each of which reference isincorporated herein by reference in their entireties: 5-HT_(2A): Bryant,H. U. et al. (1996), Life Sci., 15:1259-1268; D2: Hall, D. A. andStrange, P. G. (1997), Brit. J. Pharmacol., 121:731-736; D1: Zhou, Q. Y.et al. (1990), Nature, 347:76-80; SERT: Park, Y. M. et al. (1999), Anal.Biochem., 269:94-104; Mu opiate receptor: Wang, J. B. et al. (1994),FEBS Lett., 338:217-222.

In general, the results are expressed as a percent of control specificbinding:

$\frac{mea{sured}{specific}{binding}}{{control}{specific}{binding}} \times 100$

and as a percent inhibition of control specific binding:

$100 - ( {\frac{mea{sured}{specific}{binding}}{{control}{specific}{binding}} \times 100} )$

obtained in the presence of the test compounds.

The IC₅₀ values (concentration causing a half-maximal inhibition ofcontrol specific binding) and Hill coefficients (nH) are determined bynon-linear regression analysis of the competition curves generated withmean replicate values using Hill equation curve fitting:

$Y = {D + \lbrack \frac{A - D}{1 + ( {C/C_{50}} )^{nH}} \rbrack}$

where Y=specific binding, A=left asymptote of the curve, D=rightasymptote of the curve, C=compound concentration, C₅₀=IC₅₀, and nH=slopefactor. This analysis was performed using in-house software andvalidated by comparison with data generated by the commercial softwareSigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc.). The inhibitionconstants (Ki) were calculated using the Cheng Prusoff equation:

${Ki} = \frac{IC_{50}}{( {1 + {L/K_{D}}} )}$

where L=concentration of radioligand in the assay, and K_(D)=affinity ofthe radioligand for the receptor. A Scatchard plot is used to determinethe K_(D).

The following receptor affinity results are obtained:

Ki (nM) or maximum inhibition Receptor Example 1 Example 2 5-HT_(2A) 118.3 D2 47% inhibition 160 at 240 nM D1 22 50 SERT 44% inhibition 590 at240 nM Mu opiate receptor 22 11 Delta opioid No inhibition Kappa opioid16% @ 100 nM NOP (Nociceptin No inhibition Receptor)

Example 5: DOI-Induced Head Twitch Model in Mice

R-(−)-2,5-dimethoxy-4-iodoamphetamine (DOI) is an agonist of theserotonin 5-HT₂ receptor family. When administered to mice, it producesa behavioral profile associated with frequent head twitches. Thefrequency of these head twitches during a predetermined period of timecan be taken as an estimate of 5-HT₂ receptor agonism in the brain.Conversely, this behavioral assay can be used to determine 5-HT₂receptor antagonism in the brain by administering the DOI with orwithout an antagonist and recording the reduction in DOI-induced headtwitches after the administration of the antagonist.

The method of Darmani et al., Pharmacol Biochem Behav. (1990) 36:901-906(the contents of which are incorporated by reference in their entirety)is used with some modifications. (±)-DOI HCl is injected subcutaneouslyand the mice are immediately placed in a conventional plastic cage. Thenumber of head twitches is counted during 6 min, beginning 1 min afterDOI administration. The tested compound is administered orally 0.5 hrbefore the injection of DOI. Results area calculated as the EC50 forreducing DOI-induced head twitches. The results are shown in thefollowing Table:

EC₅₀ Compound (mg/kg, p.o.) Example 1 0.23 Example 2 0.44

The results show that the compounds of Example 1 and 2 potently blockDOI head twitch, consistent with the in-vitro 5-HT_(2A) results shown inExample 4.

Example 6: Mouse Tail Flick Assay

The Mouse Tail Flick Assay is a measure of analgesia, indicated by thepain reflex threshold of restrained mice. Male CD-1 mice are positionedwith their tails under a focused beam of a high-intensity infrared heatsource, resulting in heating of the tail. The animal can withdraw itstail from the heat source at any time that it becomes uncomfortable. Theamount of time (latency) between turning on the heating instrument andthe flicking of the mouse's tail out of path of the heat source isrecorded. Administration of morphine results in analgesia, and thisproduces a delay in the mouse's reaction to the heat (increasedlatency). Prior administration of a morphine receptor (MOR) antagonist,i.e., naloxone (NAL), reverses the effect and results in normal latencytime. This test is used as a functional assay to gauge antagonism ofmu-opiate receptors.

Example 6a: Antagonism of Morphine-Induced Analgesia by Compounds ofExamples 1 and 2

Ten male CD-1 mice (about 8 weeks of age) are assigned to each of fivetreatment groups. The groups are treated as follows: Group (1) [negativecontrol]: administered 0.25% methylcellulose vehicle p.o., 60 minutesbefore the tail flick test, and saline vehicle 30 minutes before thetail flick test; Group (2) [positive control]: administered 0.25%methylcellulose vehicle p.o., 60 minutes before the test, and 5 mg/kgmorphine in saline 30 minutes before the test; Group (3) [positivecontrol]: administered 3 mg/kg naloxone in saline 50 minutes before thetest, and 5 mg/kg morphine in saline 30 minutes before the test; Groups(4)-(6): administered either 0.1 mg/kg, 0.3 mg/kg or 1 mg/kg of the testcompound in 0.25% methylcellulose vehicle p.o., 60 minutes before thetest, and 5 mg/kg morphine in 30 minutes before the test. The experimentis repeated for the compounds of Example 1 and Example 2. The resultsare shown in the following table as mean latency measured in seconds:

Group 4 Group 5 Group 6 Group 1 Group 2 Group 3 Cmpd/Mor Cmpd/MorCmpd/Mor Veh/Veh Veh/Mor Nal/Mor (0.1 mg/kg) (0.3 mg/kg) (1 mg/kg) Ex. 11.028 9.361 2.496 8.870 6.907 6.240 Ex. 2 0.887 8.261 3.013 6.947 5.8536.537

The results demonstrate that the compounds of Example 1 and Example 2both exert a dose-dependent blockade of morphine-induced mu-opiatereceptor activity.

Example 6b: Analgesia by Compound of Example 2, Inhibited by Naloxone

In a second study using the mouse tail flick assay as described above,the compound of Example 2 is further compared at doses of 1.0 mg/kg, 3.0mg/kg and 10 mg/kg against morphine at 5 mg/kg with and withoutpre-dosing with naloxone at 3 mg/kg (intraperitoneal). In thepre-treatment groups, the naloxone is administered 20 minutes prior tothe tail flick test. In the non-pre-treatment controls, saline isadministered 20 minutes prior to the tail flick test. In each group, thevehicle, morphine or compound of Example 2 is administered 30 minutesbefore the tail flick test. The results are shown in the table below asmean latency in seconds:

Ex. 2 at Ex. 2 at Ex. 2 at Vehicle Morphine 1 mg/kg 3 mg/kg 10 mg/kgSaline pre- 0.9 9.8 4.1 7.4 9.8 treatment Naloxone pre- 0.8 1.5 1.3 1.72.1 treatment

It is found that administration of the compound of Example 2 at alldoses significantly increased the latency to tail flick, and that thiseffect is attenuated by pre-treatment with naloxone. This resultdemonstrates a dose-dependent analgesic effect produced by the Compoundof Example 2, and further suggests that this effect is mediated bymu-opioid receptor agonism.

Example 6c: Time Course for Analgesia, Compound of Example 2

The tail flick assay as described above is repeated to determine thetime course of analgesia resulting from administration of the compoundof Example 2. Mice are administered s.c. either (1) vehicle 30 minutesprior to assay, (2) 5 mg/kg morphine 30 minutes prior to assay, or(3)-(7) the 1 mg/kg of compound of Example 3 30 minutes, 2 hours, 4hours, 8 hours or 24 hours prior to assay. The results are shown in thetable below as mean latency in seconds:

Treatment TF Latency (s) Vehicle, 30 min prior 1.30 Morphine, 30 minprior 7.90 Cmpd. Ex. 2, 30 min prior 5.77 Cmpd. Ex. 2, 2 h prior 2.42Cmpd. Ex. 2, 4 h prior 1.48 Cmpd. Ex. 2, 6 h prior 1.36 Cmpd. Ex. 2, 24h prior 1.29

The results show that the Compound of Example 2 produces effectiveanalgesia when administered 30 minutes or 2 hours prior to the tailflick assay (ANOVA, P<0.001 vs. vehicle). When administered 4 hours, 8hours, or 24 hours prior to the tail flick assay, the compound ofExample 2 at 1 mg/kg does not produce an analgesic effect significantlydifferent from the vehicle control. Thus, the compound of Example 2 doesnot produce prolonged analgesia, which means that it would have a lowerpotential for abuse and a lower risk of drug-drug interactions comparedto other opiate analgesics.

Example 6d: Analgesia from Chronic Administration of the Compound ofExample 2

The tail flick assay described above is repeated using a test model inwhich animals receive a 14-day chronic treatment regimen, followed by anacute treatment 30 minutes prior to the tail flick assay. The mice aredivided into three broad groups with six sub-groups of 10 mice each. Thethree groups receive as the chronic treatment either (A) vehicle, (B)compound of Example 2 at 0.3 mg/kg, or (C) compound of Example 2 at 3.0mg/kg. Each sub-group further receives as the acute treatment either (1)vehicle, or (2)-(6) the compound of Example 2 at 0.01, 0.03, 0.1, 0.3 or1.0 mg/kg. All treatments are administered s.c. The results are shown inthe table below as mean latency to tail flick in seconds:

Group Chronic Treatment Acute Treatment Latency (s) (A) Vehicle Vehicle1.09 Vehicle Ex. 2, 0.01 mg/kg 1.87 Vehicle Ex. 2, 0.03 mg/kg 2.50Vehicle Ex. 2, 0.1 mg/kg 5.26 Vehicle Ex. 2, 0.3 mg/kg 8.26 Vehicle Ex.3, 1.0 mg/kg 9.74 (B) Ex. 3, 0.3 mg/kg Vehicle 0.893 Ex. 3, 0.3 mg/kgEx. 2, 0.01 mg/kg 1.66 Ex. 3, 0.3 mg/kg Ex. 2, 0.03 mg/kg 1.30 Ex. 3,0.3 mg/kg Ex. 2, 0.1 mg/kg 2.60 Ex. 3, 0.3 mg/kg Ex. 2, 0.3 mg/kg 3.93Ex. 3, 0.3 mg/kg Ex. 2, 1.0 mg/kg 5.64 (C) Ex. 3, 3.0 mg/kg Vehicle 1.04Ex. 3, 3.0 mg/kg Ex. 2, 0.01 mg/kg 1.64 Ex. 3, 3.0 mg/kg Ex. 2, 0.03mg/kg 1.80 Ex. 3, 3.0 mg/kg Ex. 2, 0.1 mg/kg 3.94 Ex. 3, 3.0 mg/kg Ex.2, 0.3 mg/kg 4.84 Ex. 3, 3.0 mg/kg Ex. 2, 1.0 mg/kg 7.94

It is found that 0.1, 0.3 and 1.0 mg/kg acute treatment with thecompound of Example 2 produces a statistically significantdose-dependent analgesic effect compared to in-group acute treatmentwith vehicle. This is true for each of the chronic groups (A), (B) and(C). As compared to pre-treatment with vehicle, pre-treatment with thecompound of Example 2 at 0.3 mg/kg or 3.0 mg/kg generally showed astatistically significant decrease in tail flick latency when the sameacute treatment subgroups are compared. These results demonstrate thatwhile some tolerance to the analgesic effect of the compound of Example2 occurs after 14-days of chronic treatment, the analgesia obtainedremains effective despite chronic pre-treatment.

Example 7: CNS Phosphoprotein Profile

A comprehensive molecular phosphorylation study is also carried out toexamine the central nervous system (CNS) profile of the compounds ofExample 1 and Example 2. The extent of protein phosphorylation forselected key central nervous system proteins is measured in mice nucleusaccumbens. Examined proteins include ERK1, ERK2, Glu1, NR2B and TH(tyrosine hydroxylase), and the compounds of Example 1 and 3 werecompared to the antipsychotic agents risperidone and haloperidol.

Mice were treated with the compound of Example 1 or 2 at 3 mg/kg, orwith haloperidol at 2 mg/kg. Mice were killed 30 minutes to 2 hourspost-injection by focused microwave cranial irradiation, which preservesbrain phosphoprotein as it exists at the time of death. Nucleusaccumbens was then dissected from each mouse brain, sliced and frozen inliquid nitrogen. Samples were further prepared for phosphoproteinanalysis via SDS-PAGE electrophoresis followed byphosphoprotein-specific immunoblotting, as described in Zhu H, et al.,Brain Res. 2010 Jun. 25; 1342:11-23. Phosphorylation at each site wasquantified, normalized to total levels of the protein(non-phosphorylated), and expressed as percent of the level ofphosphorylation in vehicle-treated control mice.

The results demonstrate that neither the compound of Example 1 nor ofExample 2 has a significant effect on tyrosine hydroxylasephosphorylation at Ser40 at 30 minutes or 60 minutes, in contrast tohaloperidol which produces a greater than 400% increase, and risperidonewhich produces a greater than 500% increase, in TH phosphorylation. Thisdemonstrates that inventive compounds do not disrupt dopaminemetabolism.

The results further demonstrate that neither the compound of Example 1nor of Example 2 has a significant effect on NR2B phosphorylation atTyr1472 at 30-60 minutes. The compounds produce a slight increase inGluR1 phosphorylation at Ser845, and a slight decrease in ERK2phosphorylation at Thr183 and Tyr185. Protein phosphorylation at varioussites in particular proteins are known to be linked to variousactivities of the cell such as protein trafficking, ion channelactivity, strength of synaptic signaling and changes in gene expression.Phosphorylation the Tyr1472 in the NMDA glutamate receptor has beenshown to be essential for the maintenance of neuropathic pain.Phosphorylation of Ser845 of the GluR1 AMPA type glutamate receptor isassociated with several aspects of strengthening synaptic transmissionand enhanced synaptic localization of the receptor to support long termpotentiation associated with cognitive abilities. It has also beenreported that phosphorylation of this residue results in an increasedprobability of channel opening. Phosphorylation of ERK2 kinase, a memberof the MAP kinase cascade, at residues T183 and Y185 is required forfull activation of this kinase, ERK2 is involved in numerous aspects ofcell physiology including cell growth, survival and regulation oftranscription. This kinase has been reported to be important insynaptogenesis and cognitive function.

Example 8: Mouse Marble-Burying Study (OCD Model)

The marble burying test is used to measure repetitive andanxiety-related behavior in rodents. It is based on the observation thatrats and mice will bury either harmful or harmless objects in theirbedding, and it has been used as an animal model to measure the effectof pharmacological interventions in treatment of repetitive behaviordisorders, such as OCD.

Mice are first divided up into four treatment groups: (1) vehiclenegative control, (2) 0.3 mg/kg compound of Example 2, (3) 1.5 mg/kgcompound of Example 2, and (4) 20 mg/kg MPEP(2-methyl-6-(phenylethynyl)pyridine) positive control. MPEP is aselective mGluR5 glutamate receptor antagonist. Mice in groups (2) and(3) are orally administered the compound of Example 2 at the stateddosage in a 0.5% methylcellulose aqueous vehicle 30 minutes prior to thetest. Mice in groups (1) are orally administered the vehicle, and micein group (4) are given an intraperitoneal injection of MPEP just priorto the start of the test.

The test is conducted in rectangular cages with 4-5 cm of wood chipbedding in a room with the window shades lowered and the door closed tominimize distractions. Fifteen clean marbles are evenly spaced on top ofthe bedding in three rows of five marbles. One mouse is placed in eachcage. The mouse and cage is left undisturbed for 30 minutes. At the endof the test, the mouse is removed and the number of marbles buried to atleast ⅔ of their depth is counted. The results are shown in thefollowing table:

Group Marbles Buried (1) Vehicle 13.2 (2) 0.3 mg/kg Ex. 2 9.3 (3) 1.5mg/kg Ex. 2 4.7 (4) MPEP 0.2

The result demonstrate that compared to the control, there is astatistically significant decrease in marble burying for the micetreated with 0.3 mg/kg of the compound of Example 2 (p<0.01) and with1.5 mg/kg of the compound of Example 2 (p<0.001). In addition, there isa clear dose-response relationship evident. The results support theutility of the compound of Example 2 in OCD therapeutic indications.

Example 9: Mu-Opiate Receptor Activity Assays

The compounds of Example 1 and 2 are tested in CHO-K1 cells expressinghOP3 (human mu-opiate receptor 1 subtype) using an HTRF-based cAMP assaykit (cAMP Dynamic2 Assay Kit, from Cisbio, #62AM4PEB). Frozen cells arethawed in a 37° C. water bath and are resuspended in 10 mL of Ham's F-12medium containing 10% FBS. Cells are recovered by centrifugation andresuspended in assay buffer (5 nM KCl, 1.25 mM MgSO₄, 124 mM NaCl, 25 mMHEPES, 13.3 mM glucose, 1.25 mM KH₂PO₄, 1.45 mM CaCl₂, 0.5 g/Lprotease-free BSA, supplemented with 1 mM IBMX). Buprenorphine, amu-opiate receptor partial agonist, and naloxone, a mu-opiate receptorantagonist, and DAMGO, a synthetic opioid peptide full agonist, are runas controls.

For agonist assays, 12 μL of cell suspension (2500 cells/well) are mixedwith 6 μL forksolin (10 μM final assay concentration), and 6 μL of thetest compound at increasing concentrations are combined in the wells ofa 384-well white plate and the plate is incubated for 30 minutes at roomtemperature. After addition of lysis buffer and one hour of furtherincubation, cAMP concentrations are measured according to the kitinstructions. All assay points are determined in triplicate. Curvefitting is performed using XLfit software (IDBS) and EC₅₀ values aredetermined using a 4-parameter logistic fit. The agonist assay measuresthe ability of the test compound to inhibit forskolin-stimulated cAMPaccumulation.

For antagonist assays, 12 μL of cell suspension (2500 cells/well) aremixed with 6 μL of the test compound at increasing concentrations, andcombined in the wells of a 384-well white plate and the plate isincubated for 10 minutes at room temperature. 6 μL of a mixture of DAMGO(D-Ala²-N-MePhe⁴-Gly-ol-enkephelin, 10 nM final assay concentration) andforksolin (10 μM final assay concentration) are added, and the platesare incubated for 30 minutes at room temperature. After addition oflysis buffer, and one hour of further incubation, cAMP concentrationsare measured according the kit instructions. All assay points aredetermined in triplicate. Curve fitting is performed using XLfitsoftware (IDBS) and IC₅₀ values are determined using a 4-parameterlogistic fit. Apparent dissociation constants (K_(B)) are calculatedusing the modified Cheng-Prusoff equation. The antagonist assay measuresthe ability of the test compound to reverse the inhibition offorskolin-induced cAMP accumulation caused by DAMGO.

The results are shown in the Table below. The results demonstrate thatthe compound of Example 2 is a weak antagonist of the Mu receptor,showing much higher IC₅₀ compared to naloxone, and that it is amoderately high affinity, but partial agonist, showing only about 22%agonist activity relative to DAMGO (as compared to about 79% activityfor buprenorphine relative to DAMGO). The compound of Example 1 is alsoshown to have moderately strong partial agonist activity.

Antagonist Agonist K_(B) Compound IC₅₀ (nM) EC₅₀ (nM) (nM) Naloxone  5.80 —  0.65 DAMGO — 1.56 — Buprenorphine — 0.95 — Cmpd. Ex. 2 64164.5 71.4 Cmpd Ex. 1 — 140 —

Buprenorphine is a drug used for chronic pain treatment and for opiatewithdrawal, but it suffers from the problem that users can becomeaddicted due to its high partial agonist activity. To offset this, thecommercial combination of buprenorphine with naloxone is used (sold asSuboxone). Without being bound by theory, it is believed that thecompounds of the present invention, which are weaker partial Mu agoniststhan buprenorphine, with some moderate antagonistic activity, will allowa patient to be more effectively treated for pain and/or opiatewithdrawal with lower risks of addiction.

In additional related study using a recombinant human MOP-beta-arrestingsignaling pathway, it is found that the Compound of Example 2 does notstimulate beta-arrestin signaling via the MOP receptor at concentrationsup to 10 μM, but that it is an antagonist with an IC₅₀ of 0.189 μM. Incontrast, the full opioid agonist Met-enkephalin stimulatesbeta-arrestin signaling with an EC₅₀ of 0.08 μM.

Example 10: Rat Tolerance/Dependence Study

The compound of Example 2 is assessed during repeated (28 day) dailysubcutaneous administration to male Sprague-Dawley rats to monitor drugeffects on dosing and to determine if pharmacological tolerance occurs.In addition, behavioral, physical and physiological signs in the rats ismonitored following abrupt cessation of repeated dosing to determinewhether the compound induces physical dependence on withdrawal. Further,a pharmacokinetic study is performed in parallel with the tolerance anddependence study to determine the plasma drug exposure levels of thecompound at the specific doses used in the tolerance and dependencestudy. Morphine is used as a positive control to ensure validity of themodel and as a reference comparator from a similar pharmacologicalclass.

The compound of Example 2 is evaluated at two doses, 0.3 and 3 mg/kg,administered subcutaneously four times per day. Repeated administrationis found to produce peak plasma concentrations of 15 to 38 ng/mL(average, n=3) for 0.3 mg/kg dosing, and 70 to 90 ng/mL (average, n=3)for 3 mg/kg dosing. Peak concentration is reached at 30 minutes to 1.5hours post-administration with comparable results obtained on the 1st,14th and 28th day of administration.

At both doses of Example 2, it is found that there is no significanteffect on animal body weight, food and water intake or body temperatureduring either the on-dose or withdrawal phase. The predominantbehavioral and physical effects caused by repeated administration at 0.3mg/kg is found to be hunched posture, Straub tail and piloerectionduring the dosing phase. At the higher dose, the main behavioral andphysical signs observed are hunched posture, subdued behavior, Straubtail, tail rattle and piloerection.

A similar profile of behavioral and physical signs is observed followingabrupt cessation of the compound on Day 28 of the study. While rearingand increased body tone were not observed during the on-dose phase forat 0.3 mg/kg, it is found to be significantly increased during thewithdrawal phase. At the higher dose, mild rearing is observed duringthe on-dose phase, but during the withdrawal phase, rearing is morepronounced and increased body tone is observed.

As a positive control, morphine is doses at 30 mg/kg orally twice perday. This dosing regimen, as expected, is observed to be associated withchanges in body weight, food and water intake, rectal temperature andclinical signs consistent with the development of tolerance andwithdrawal-induced dependence. Body weight was significantly increasedcompared with the vehicle-treated control group on Days 2 and 3, whileit was significantly decreased from Day 5. Morphine decreased foodintake significantly on Days 1-9. Thereafter food intake is generallyobserved to be lower than for the control group, but was notsignificantly different from controls on Days 9, 13, 14 16, 18, 21, 22and Day 25. These effects on body weight and food intake demonstratetolerance to the effect of morphine.

Water intake of the morphine-treated group is also found to besignificantly lower than the control group on 25 out of 28 days duringthe on-dose phase. Body temperature is also generally lower than thecontrol group during the on-dose phase, significantly so on Days 20, 21and 27. The predominant behavioral effects induced by morphine duringthe on-dose phase are observed to be Straub tail, jumping, digging,increased body tone, increased locomotor activity, explosive movementsand exopthalmus.

Furthermore, withdrawal of morphine administration on Day 28 is observedto result in an initial further decrease in food intake followed byrebound hyperphagia, with significantly increased food intake on Day 33versus the control group. Food intake returns to control levels by Day35. Similarly, rats which had previously received morphine also areobserved to have an initial reduction in water intake on Day 29,followed by rebound hyperdipsia (water consumption returns to controllevels by Day 31). In addition, statistically significant decreases inrectal body temperature are observed during dosing, but body temperaturereturns to control levels during the withdrawal phase.

Moreover, new behavioral and physical signs are observed during thewithdrawal phase from morphine, and this demonstrates the presence ofdependence. These signs include piloerection, ataxia/rolling gait, wetdog shakes and pinched abdomen. Other abnormal behaviors observed duringthe on-dose phase gradually disappear during the withdrawal phase. ByDay 35, rearing was the only behavior or physical sign observed withhigh incidence in the rats that had previously received morphine.

Thus, repeated morphine administration is shown to produce clear signsof tolerance and dependence in this study, with changes in body weight,food and water intake, rectal temperature and clinical signs consistentwith the development of tolerance and withdrawal induced dependence.This demonstrates the validity of the study method in detectingphysiological alterations during administration and cessation of dosing.

In contrast, repeated administration of the Compound of Example 2, atboth 0.3 and 3 mg/kg four times, does not produce tolerance duringsubcutaneous dosing for 28 days. Furthermore, on withdrawal, a similarbut decreasing profile of behavioral and physical signs is observed atthe highest dose, which is not considered to be of clinicalsignificance. Thus, overall the Compound of Example 2 was found not toproduce a syndrome of physical dependence upon cessation of dosing.

Example 11: Oxycodone-Dependent Withdrawal Study in Mice

Oxycodone is administered to male C57BL/6J mice for 8 days at anincreasing dose regimen of 9, 17.8, 23.7, and 33 mg/kg b.i.d. (7 hoursbetween injections) on days 1-2, 3-4, 5-6 and 7-8 respectively. On themorning of the ninth day, the mice are administered the compound ofExample 3 at either 0.3, 1 or 3 mg/kg subcutaneous. This is followed 30minute later by either an injection of vehicle or with an injection of 3mg/kg of naloxone. Another cohort of mice serve as negative controls,and instead of oxycodone, these mice are administered saline on days 1to 8. On day 9, these mice are administered either vehicle (followed bynaloxone, as above) or the compound of Example 2 at 3 mg/kg, s.c.(followed by naloxone, as above).

On day 9, immediately after the injection of naloxone (or vehicle), themice are individually placed in clear, plastic cages and are observedcontinuously for thirty minutes. The mice are monitored for commonsomatic signs of opiate withdrawal, including jumping, wet dog shakes,paw tremors, backing, ptosis, and diarrhea. All such behaviors arerecorded as new incidences when separated by at least one second or wheninterrupted by normal behavior. Animal body weights are also recordedimmediately before and 30 minutes after the naloxone (or vehicle)injections. Data is analyzed with ANOVA followed by the Tukey test formultiple comparisons, when appropriate. Significant level is establishedat p<0.05.

The results are shown in the Table below:

Dosing: (1) on days 1-8, Total Body (2) on day 9, followed by Number ofPaw Weight (3) 30 minutes later Signs Tremors Jumps Loss (1) Saline; (2)Vehicle, 2.2 0.87 0 0.5% (3) Naloxone (1) Saline; (2) Compound 5.3 0.120 0.4% 3.0 mg/kg, (3) Naloxone (1) Oxycodone; (2) 155.1 73.6 63.2 7.8%Compound 3.0 mg/kg, (3) Vehicle (1) Oxycodone; (2) 77.5 19.6 40.6 7.5%Compound 0.3 mg/kg, (3) Naloxone 3 mg/kg (1) Oxycodone; (2) 62.5 14.834.8 6.0% Compound 1.0 mg/kg, (3) Naloxone 3 mg/kg (1) Oxycodone; (2)39.5 0.5 26.6 4.0% Compound 3.0 mg/kg, (3) Naloxone 3 mg/kg

Total number of signs includes paw tremors, jumps, and wet dog shakes.In oxycodone-treated mice, it is found that naloxone elicits asignificant number of total signs, paw tremors, jumps and body weightchange (p<0.0001 for each). At all doses tested, the compound of Example2 produces a significant decrease in total number of signs and pawtremors. In addition, at 3.0 mg/kg, the compound also produces asignificant decrease in jumps and attenuated body weight loss.

These results demonstrate that the compound of Example 2dose-dependently reduces the signs and symptoms of opiate withdrawalafter the sudden cessation of opiate administration in opiate-dependentrats.

Example 12: Formalin Paw Test (Inflammatory Pain Model)

Sub-plantar administration of chemical irritants, such as formalin,causes immediate pain and discomfort in mice, followed by inflammation.Subcutaneous injection of 2.5% formalin solution (37 wt % aqueousformaldehyde, diluted with saline) into the hind paw results in abiphasic response: an acute pain response and a delayed inflammatoryresponse. This animal model thus provides information on both acute painand sub-acute/tonic pain in the same animal.

C57 mice are first habituated in an observation chamber. 30 minutesprior to formalin challenge, mice are administered either vehicleinjected subcutaneously, 5 mg/kg of morphine (in saline) injectedsubcutaneously, or the compound of Example 2 (in 45% w/v aqueouscyclodextrin) injected subcutaneously at either 0.3, 1.0 or 3.0 mg/kg.In addition, another set of mice are treated with the control vehicle orthe compound of Example 2 at 3.0 mg/kg, via oral administration, ratherthan subcutaneous injection.

The mice are then given a subcutaneous injection into the plantarsurface of the left hind paw of 20 μL of 2.5% formalin solution. Overthe next 40 minutes, the total time spent licking or biting the treatedhind-paw is recorded. The first 10 minutes represent the acutenociceptic response, while the latter 30 minutes represents the delayedinflammatory response. At one minter intervals, each animal's behavioris assessed using “Mean Behavioral Rating,” which is scored on a scaleof 0 to 4:

0: no response, animal sleeping

1: animal walking lightly on treated paw, e.g., on tip-toe

2: animal lifting treated paw

3: animal shaking treated paw

4: animal licking or biting treated paw

Data are analyzed by ANOVA followed by post-hoc comparisons with Fishertests, where appropriate. Significance is established at p<0.05.

The results are shown in the Table below.

Mean Behavior Rating (0-4) Mean Licking Time (min) 0-10 11-40 0-6 16-400-10 11-40 0-6 16-40 Min min min min min min min min Vehicle 1.4 1.4 2.11.5 34 75 32 76 (SC) Vehicle 1.2 0.9 1.9 1.0 29 50 33 40 (PO) Morphine1.1 0.2 1.7 0.2 11 0 11 0 Cmpd, SC 1.5 1.0 2.3 1.2 31 68 34 70 0.3 mg/kgCmpd, SC 1.3 1.0 1.9 1.1 26 60 26 65 1.0 mg/kg Cmpd, SC 0.8 0.1 1.3 0.114 36 11 36 3.0 mg/kg Cmpd, PO 0.9 0.8 1.5 0.9 11 3 9 3 3.0 mg/kg

The results demonstrate a significant treatment effect during both theearly phase (0-10 min) and late phase (11-40 min) response periods.Post-hoc comparisons show that, compared to vehicle treatment,subcutaneous injection of morphine or the compound of Example 2 (at 3mg/kg) significantly attenuates the pain behavior rating induced byformalin injection, as well as significantly reducing licking time.Post-hoc comparisons also show that subcutaneous injection of morphineor the compound of Example 2 (at 3 mg/kg), as well as the compound ofExample 2 orally (at 3 mg/kg), significantly reduces time spent licking.While the mean pain behavior rating was also reduced using 1.0 mg/kg ofcompound subcutaneous and at 3.0 mg/kg oral, these effects were notstatistically significant in this study. Licking time was similarlyreduced using 1.0 mg/kg of the compound of Example 2 subcutaneously, butthe result was not statistically significant in this study. It was alsofound that no mice in the study underwent significant changes in bodyweight in any of the study groups.

Example 13: Self Administration in Heroin-Maintained Rats

A study is performed to determine whether heroin-addicted ratsself-administer the compound of Example 2, and it is found that they donot, further underscoring the non-addictive nature of the compounds ofthe present disclosure.

The study is performed in three stages. In the first stage, rats arefirst trained to press a lever for food, and they are then provided withan in-dwelling intravenous jugular catheter and trained toself-administer heroin. In response to a cue (the lighting of a light inthe cage), three presses of the lever by the animal results in a singleheroin injection via the catheter. The heroin is provided at an initialdose of 0.05 mg/kg/injection, and later increased to 0.015mg/kg/injection. This trained response is then extinguished by replacingthe heroin supply with saline. In the second phase, the saline solutionis replaced by a solution of the compound of Example 2, at one of fourdoses: 0.0003 mg/kg/injection, 0.001 mg/kg/injection, 0.003mg/kg/injection, and 0.010 mg/kg/injection. Each individual rat isprovided with either one or two different doses of the compound inrising fashion. This response is then extinguished with salineinjections, followed by the third phase, which repeats the use of heroinat 0.015 mg/kg/injection. The purpose of the third phase is todemonstrate that the rats still show addictive behavior to heroin at theend of the study. The study results are shown in the table below:

Animals Mean Lever Treatment (n) presses Saline Extinction 1 21 4.08Heroin Acquisition (0.015 mg/kg/inj) 21 19.38* Cmpd. Ex. 2 at 0.0003mg/kg/inj 8 3.17** Cmpd. Ex. 2 at 0.0003 mg/kg/inj 8 3.29** Cmpd. Ex. 2at 0.0003 mg/kg/inj 8 3.99** Cmpd. Ex. 2 at 0.0003 mg/kg/inj 8 4.87**Saline Extinction 2 19 3.60** Heroin Reinstatement (0.015 mg/kg/inj) 1917.08** *P < 0.001 for heroin acquisition vs. saline extinction 1(multiple t test); **P < 0.001 for Cmpd of Ex. 2 vs. heroin acquisition(Dunnett's test); P > 0.7 for all comparisons between Cmpd. of Ex. 2 andsaline extinction 1 (William's test)

The results demonstrate that there is a statistically significantincrease in lever pressing by the rats when being administered heroin,but that there was no significant difference when being administeredsaline or the compound of Example 2. Thus, the results suggest that ratsdo not become addicted to the compound of Example 2.

Example 14: Animal Pharmacokinetic Data

Using standard procedures, the pharmacokinetic profile of the compoundof Example 2 is studied in several animals.

Example 14a: Rat PK Studies

In a first study, rats are administered the compound of Example 2 eitherby intravenous bolus (IV) at 1 mg/kg in 45% Trapposol vehicle, or orally(P0) at 10 mg/kg in 0.5% CMC vehicle (N=3 each group). In a secondstudy, rats are administered the compound of Example 2 at 10 mg/kg PG or3 mg/kg subcutaneously (SC), each in 45% Trapposol vehicle (N=6 for eachgroup). Plasma concentrations of the drug are measured at time pointsfrom 0 to 48 hours post dose. Representative results are tabulated below(* indicates plasma concentration below measurable level ofquantitation):

Study One Study Two IV PO PO SC (1 mg/kg) (10 mg/kg) (10 mg/kg) (3mg/kg) 30 min (ng/mL) 99.0 30.7 54.9 134.4 1 hour (ng/mL) 47.3 37.2 60.6140.9 6 hours (ng/mL) 1.1 9.4 21.0 18.2 24 hours (ng/mL) * 0.1 0.4 1.948 hours (ng/mL) * * ND ND Cmax (ng/mL) 314.8 37.2 60.6 140.9 AUC(ng-hr/mL) 182 215 409 676 Bioavailability 100% 12% 22% 123% t-½ (hr)3.1 9.5

Example 14b: Mice PK Studies

A similar study in mice is performed using 10 mg/kg PO administration ofthe compound of Example 2, and the following results are obtained:Tmax=0.25 hours; Cmax=279 ng/mL; AUC (0-4 h)=759 ng-hr/mL; blood-plasmaratio (0.25-4 h) ranges from 3.7 to 6.6. The study is also conducted ata dose of 0.1 mg/kg SC. Representative results are shown in the tablebelow:

Study: PO, 10 mg/kg SC, 0.1 mg/kg (0.5% CMC veh) (45% Trapposol veh)Plasma Brain Plasma Brain Time (hr) (ng/mL) (ng/g) (ng/mL) (ng/g) 0.25279 1288 27.5 57.1 0.5 179 1180 31.1 71.9 1 258 989 29.2 78.5 2 153 69914.6 38.7 4 199 734 4.7 32.6 Tmax (hr) 0.25 0.25 0.5 1.0 Cmax (ng/mL)279 1288 31.1 78.5 AUC0-4 h 759 2491 67 191 (ng-hr/mL) B/P Ratio 3.3 2.8

Together these results show that the compound of Example 2 iswell-absorbed and distributed to the brain and tissues and is retainedwith a reasonably long half-life to enable once-daily administration oftherapeutic doses.

Example 15: Gastrointestinal Function

The effect of the compound of Example 2 on gastrointestinal motility inrats is examined by monitoring the rate of intestinal transit of anactivated charcoal bolus. Rats were treated with either (1) aqueouscarboxymethyl cellulose vehicle, (2) morphine (5 mg/kg, SC), or (3) thecompound of Example 3 (at 0.3, 1.0 or 3.0 mg/kg, SC) 30 minutes prior toan oral bolus of 15% aqueous activated charcoal. The measured outcome ismotility ratio, calculated as the distance traveled by the charcoal as afraction of the full length of the animal's intestine. The results areshown in the table below:

Group Motility (n = 10 each) Treatment Ratio 1 Vehicle 0.55 2 Cmpd. Ex.2, 0.3 mg/kg 0.50 3 Cmpd. Ex. 2, 1 mg/kg 0.55 4 Cmpd. Ex. 2, 3 mg/kg0.50 5 Morphine, 5 mg/kg 0.27

These results show that the compound of Example 2 has no significanteffect on gastrointestinal motility at a dose up to 3 mg/kg. Incontrast, and as expected, morphine results in approximately a 50%reduction in gastric motility.

In a further experiment, rats were pre-treated 60 minutes prior to thecharcoal bolus with either vehicle, morphine (5 mg/kg), or the compoundof Example 2 (3 mg/kg), each SC, followed by treatment with eithermorphine (5 mg/kg), morphine plus compound of Ex. 2 (0.3 mg/kg or 3mg/kg), or compound of Ex. 2 (3 mg/kg) alone. The results are shown inthe table below. For groups 2 and 3, morphine was injected first,followed immediately by the injection of the compound of Example 2:

Group Motility (n = 8 each) Pre-Treatment Treatment Ratio 1 VehicleMorphine, 5 mg/kg 0.21 2 None Morphine, 5 mg/kg + 0.26 Cmpd. Ex. 2, 0.3mg/kg 3 None Morphine, 5 mg/kg + 0.32 Cmpd. Ex. 2, 3 mg/kg 4 Morphine, 5mg/kg Cmpd. Ex. 2, 3 mg/kg 0.41 5 Cmpd. Ex. 2, 3 mg/kg Morphine, 5 mg/kg0.30

The results show that the compound of Example 2 reverses the inhibitionof gastrointestinal motility caused by morphine when given eitherconcurrently or sequentially prior to morphine, with the blockade ofmorphine's effect stronger when pre-treatment is used.

Without being bound by theory, it is believed that these differencesresult from the compound of Example 2 acting as biased MOP ligands andits failure to activate beta-arrestin signaling pathways downstream,which pathways have been shown to mediate opiate-linked side effects,including constipation and respiratory depression.

Example 16: Pulmonary Function

The effect of the compound of Example 2 on pulmonary function in rats isexamined by monitoring respiratory rate, tidal volume and minute volumein rats following the subcutaneous administration of the compound ofExample 2 at 0.3, 1.0 and 3.0 mg/kg, compared to vehicle control.Measurements are taken at 0, 15, 60, 120, and 240 minutes followingadministration of the compound. It is found that there are nosignificant differences between the vehicle and any of the test groupsat any time point. Results are shown below for 60 minutes, which istypical of the results obtained:

RR TV MV (breaths/min) (mL) (mL/min) Vehicle 188 1.10 195 Cmpd. Ex. 2,0.3 mg/kg 181 1.06 181 Cmpd. Ex. 2, 1.0 mg/kg 203 0.86 169 Cmpd. Ex. 2,3.0 mg/kg 190 0.97 179

Example 17: Synthesis of 1-(Acyloxy)Alkyl Derivatives

A series of compounds according to Formula I, wherein Z is —O— andwherein R⁵ is —C(R⁶)(R⁷)—O—C(O)—R⁸, and wherein R⁶, R⁷ and R⁸ are asfollows, are prepared starting from the precursor Compound 14a:

Compound R⁶ R⁷ R⁸ 17b H H CH₃(CH₂)₁₀ 17c H H CH₃(CH₂)₁₄

Each compound is prepared by reacting Compound 17a,(6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one,with the appropriate chloromethyl alkylate 17x (R⁸CO₂C(R⁶)(R⁷)Cl). Thenecessary chloromethyl alkylates are each prepared from thecorresponding acid chloride, R⁸COCl.

For example, chloromethyl dodecanoate (CH₃(CH₂)₁₀—C(O)O—CH₂Cl) isprepared as follows. To a stirred suspension of zinc(II) chloride (294mg, 2.16 mmol) and paraformaldehyde (842 mg, 28.08 mmol) in anhydrousacetonitrile (4 mL) at 0° C. is added lauryl chloride (5.0 mL, 21.6mmol) dropwise under argon. The suspension is stirred at 0° C. for 10min and at room temperature for 10 min, and then is heated up to 70° C.for 24 h. The reaction mixture is then cooled to room temperature andpoured into dichloromethane (100 mL). The resulting suspension isfiltered under vacuum and washed with dichloromethane (2×10 mL). To thecombined filtrate is added saturated sodium bicarbonate (100 mL) and themixture is stirred at room temperature for 1.5 h. The dichloromethanephase is separated and washed with saturated sodium bicarbonate (2×60mL), and evaporated to dryness under reduced pressure. The resultingresidue is further dried under high vacuum to give chloromethyldodecanoate as a light orange oil (4.523 g, 84% yield). This crudeproduct is directly used for the next reaction without furtherpurification. Chloromethyl dodecanoate is used for the preparation ofcompound 17b. For the preparation of compound 17c, chloromethylpalmitate is used, which is prepared from palmitoyl chloride andparaformaldehyde. Analogous compounds 17x may be made analogously usingother acid chlorides, such as octanoyl chloride or stearyl chloridealong other aldehydes, such as acetaldehyde, propionaldehyde orisobutyraldehyde.

Compound 17b. A suspension of potassium iodide (131 mg, 0.786 mmol),potassium carbonate (181 mg, 1.31 mmol), N,N-diisopropylethylamine (137μL, 0.786 mmol), N,N-dimethylpyridin-4-amine (64 mg, 0.524 mmol),chloromethyl dodecanoate (522 mg, 2.10 mmol), and 17a (212 mg, 0.556mmol) in anhydrous DMF (1.5 mL) is bubbled with argon for 5 min. Theresulting suspension is heated up to 125° C. by microwave for 5 h, andthe solvent is removed under reduced pressure. The obtained crudeproduct is purified by silica-gel column chromatography using a gradientof 0-100% ethyl acetate in hexane as eluent to afford((6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-2-oxo-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-3(2H)-yl)methyldodecanoate (17b) as a light orange solid (150 mg, 45% yield). MS (ESI)m/z 594.4089 [M+H]⁺. 1H NMR (500 MHz, Chloroform-d) δ 6.96 (dd, J=9.1,8.2 Hz, 2H), 6.90 (s, 1H), 6.82 (d, J=7.0 Hz, 4H), 6.16 (d, J=10.5 Hz,1H), 5.70 (d, J=10.5 Hz, 1H), 4.05 (d, J=14.5 Hz, 1H), 3.99 (d, J=6.6Hz, 2H), 3.42 (d, J=14.4 Hz, 1H), 3.38-3.25 (m, 1H), 2.91 (d, J=28.2 Hz,1H), 2.74 (s, 1H), 2.50 (s, 2H), 2.34 (t, J=7.5 Hz, 2H), 2.28 (t, J=7.9Hz, 1H), 1.96 (s, 3H), 1.86 (s, 1H), 1.70-1.59 (m, 2H), 1.54 (s, 1H),1.35-1.16 (m, 17H), 0.88 (t, J=6.9 Hz, 3H).

Compounds 17c is prepared in analogous fashion using the appropriatehalides 14x. For example, Compound 17c is obtained using chloromethylpalmitate. MS (ESI) m/z 650.4348 [M+H]+. 1H NMR (500 MHz, Chloroform-d)δ 6.96 (dd, J=9.1, 8.2 Hz, 2H), 6.89 (dd, J=5.5, 2.8 Hz, 1H), 6.86-6.78(m, 4H), 6.16 (d, J=10.5 Hz, 1H), 5.70 (d, J=10.5 Hz, 1H), 4.05 (d,J=14.5 Hz, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.41 (d, J=14.5 Hz, 1H), 3.32(d, J=5.6 Hz, 2H), 2.97-2.89 (m, 1H), 2.74 (d, J=11.3 Hz, 1H), 2.57-2.42(m, 2H), 2.34 (t, J=7.5 Hz, 2H), 2.30-2.20 (m, 1H), 2.00-1.91 (m, 3H),1.85 (t, J=11.0 Hz, 1H), 1.62 (p, J=7.4 Hz, 2H), 1.53 (s, 2H), 1.35-1.18(m, 23H), 0.88 (t, J=6.9 Hz, 3H).

Example 18: Synthesis of Alkoxycarbonyl (Carbamate) Derivatives

A series of compounds according to Formula I, wherein Z is —O— andwherein R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)), and wherein R^(a), R^(b)and R^(c) are as follows, is prepared:

Compound R^(a) R^(b) R^(c) 18a H H CH₃(CH₂)₉ 18b H H CH₃(CH₂)₁₃

Each compound is prepared by reacting Compound 17a with the appropriatealkoxycarbonyl chloride, R^(c)CH₂O(CO)Cl:

Compound 18b. A mixture of N,N-diisopropylethylamine (219 μL, 1.572mmol), N,N-dimethyl-pyridin-4-amine (64 mg, 0.524 mmol),hexadecyloxycarbonyl chloride (320 mg, 1.05 mmol), and 17a (200 mg,0.524 mmol) in anhydrous DMF (3 mL) is bubbled with argon for 5 min. Themixture is stirred at room temperature for 5 h, and the solvent isremoved under reduced pressure. The obtained residue is purified bysilica-gel column chromatography using a gradient of 0-100% ethylacetate in hexane as eluent to give the title compound as a light orangesolid (197 mg, 58% yield. MS (ESI) m/z 650.4970 [M+H]+. 1H NMR (500 MHz,Chloroform-d) δ 7.04 (d, J=8.2 Hz, 1H), 6.96 (dd, J=9.2, 8.2 Hz, 2H),6.91 (d, J=7.3 Hz, 1H), 6.86-6.76 (m, 3H), 4.40 (t, J=6.7 Hz, 2H),4.04-3.94 (m, 3H), 3.35 (d, J=14.1 Hz, 2H), 3.26 (d, J=5.3 Hz, 1H), 2.92(s, 1H), 2.74 (s, 1H), 2.50 (s, 2H), 2.24 (d, J=14.8 Hz, 1H), 2.00-1.86(m, 4H), 1.83-1.74 (m, 2H), 1.48-1.38 (m, 2H), 1.26 (s, 25H), 0.88 (t,J=6.9 Hz, 3H).

Compound 18a. Compound 18a is obtained in analogous fashion usingdodecanoxycarbonyl chloride. MS (ESI) m/z 594.4180 [M+H]+. 1H NMR (500MHz, Chloroform-d) δ 7.06 (dd, J=8.2, 0.9 Hz, 1H), 6.99-6.91 (m, 3H),6.86-6.76 (m, 3H), 4.41 (t, J=6.7 Hz, 2H), 4.00-3.96 (m, 2H), 3.53 (s,1H), 3.36 (d, J=14.0 Hz, 1H), 3.29 (d, J=4.0 Hz, 1H), 3.12 (s, 1H), 2.96(s, 1H), 2.70 (d, J=11.9 Hz, 2H), 2.48 (s, 1H), 2.19 (s, 1H), 2.13-2.02(m, 2H), 2.03-1.94 (m, 1H), 1.83-1.72 (m, 2H), 1.47-1.39 (m, 2H), 1.27(d, J=6.3 Hz, 18H), 0.88 (t, J=6.9 Hz, 3H).

Example 19: Pharmacokinetic Analysis of the Compounds 17b and 18a

Rat PK studies are performed substantially according to the sameprotocol as used in Example 14a. Rats are dosed subcutaneously with theCompound of Example 2, the Compound 17b or the Compound 18a, at 30mg/kg, in a vehicle consisting of 3% CMC, 0.1% Tween 20 in normal saline(0.9% NaCl) (N=4 for each groups). Plasma samples are taken at 2, 5, 15and 30 minutes, and at 1, 2, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168,240, 336, 504 and 720 hours. Samples are analyzed for the concentrationof the administered compound (Ex. 2, Cmpd. 17b or 18a), as well as forthe compound of Example 2 (which is the hydrolytic metabolite of theCompounds 17b and 18a). Representative results are shown in the tablebelow (* indicates an analyte level below the measurable level ofquantitation):

Administered: Cmpd Ex. 2 Cmpd 17b Cmpd 18a Analyte: Cmpd Ex. 2 Cmpd 17bCmpd Ex. 2 Cmpd 18a Cmpd Ex. 2 (ng/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL)30 minutes 9.2 1.6 7.7 1.8 1.0 1 hour 13.2 1.4 9.2 1.7 1.0 6 hours 10.90.7 7.5 1.3 0.5 24 hours 5.6 0.8 2.7 0.9 0.1 72 hours 3.9 * 1.7 0.2 0.2144 hours 6.7 * 5.0 * 0.2 336 hours 8.0 * 4.3 * * 720 hours 2.3 * 0.6 NDND Tmax (hr) 2 0.25 1 0.5 0.03 Cmax (ng/mL) 14.5 1.7 9.2 1.8 1.5 AUCobs(ng-hr/mL) 5416 18 2332 56 29

These results demonstrate that the compounds of the present disclosureundergo effective metabolic hydrolysis to yield therapeutic plasmaconcentrations of the active drug moiety, the compound of Example 2.Furthermore, the results show that these compounds undergo a gradual invivo hydrolysis which significantly prolongs the time frame over whichmeasurable plasma concentrations of the compound of Example 2 are found(by comparison to the results shown in Example 14a). For example, whenthe compound of Example 2 is administered to rats subcutaneously at thetherapeutically effective dose of 3 mg/kg, the plasma concentration ofthe drug is seen to fall to near baseline levels at 24 hours post-dosing(see Example 14a). In contrast, when the pro-drug Compound 17b isadministered at the dose of 30 mg/kg, significant plasma concentrationsof the compound of Example 2 are obtained up to 336 hours later.

1.-13. (canceled)
 14. A method for the treatment or prophylaxis of acentral nervous system disorder, comprising administering to a patientin need thereof a compound of a Formula I:

wherein: R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)),—C(O)—O—CH₂—O—C(R^(a))(R^(b))(R^(c)) or —C(R⁶)(R⁷)—O—C(O)—R⁸: Z is O, or—C(O)—; R⁸ is —C(R^(a))(R^(b))(R^(c)), —O—C(R^(a))(R^(b))(R^(c)), or—N(R^(d))(R^(e)); R^(a), R^(b) and R^(c) are each independently selectedfrom H and C₁₋₂₄alkyl; R^(d) and R^(e) are each independently selectedfrom H and C₁₋₂₄alkyl; R⁶ and R⁷ are each independently selected from H,C₁₋₆alkyl, carboxy and C₁₋₆alkoxycarbonyl; in free or pharmaceuticallyacceptable salt form; or a compound of a Formula II:

wherein: Z is O, or —C(O)—; R¹, R², R³ and R⁴ are each independentlyselected from H and C₁₋₆alkyl; n is an integer from 1 to 23; in free orpharmaceutically acceptable salt form.
 15. The method according to claim14, wherein said disorder is selected from the group consisting of adisorder selected from a group consisting of obesity, anxiety, generalanxiety, social anxiety, panic disorders, depression, refractorydepression, major depressive disorder, treatment-resistant depression,psychosis, schizophrenia, sleep disorders, sexual disorders, migraine,pain and conditions associated with pain, cephalic pain, idiopathicpain, neuropathic pain, chronic pain, fibromyalgia, chronic fatigue,agoraphobia, social phobias, agitation in dementia, agitation in autismand related autistic disorders, gastrointestinal disorders, dementia,mood disorders, drug dependencies, opiate dependency, cocainedependency, amphetamine dependency, alcohol dependency, withdrawal fromdrug or alcohol dependency, opiate overdose, co-morbidities associatedwith drug dependencies, binge eating disorder, obsessive-compulsivedisorder (OCD), obsessive-compulsive personality disorder (OCPD),compulsive gambling disorder, compulsive eating disorder, bodydysmorphic disorder, hypochondriasis, pathological grooming disorder,kleptomania, pyromania, attention deficit-hyperactivity disorder (ADHD),attention deficit disorder (ADD), impulse control disorder, andcombination thereof.
 16. The method according to claim 14, wherein saiddisorder is a disorder involving serotonin 5-HT_(2A), serotonin reuptaketransporter (SERT), dopamine D1 and/or D2 pathway and/or the μ-opioidreceptor.
 17. The method according to claim 14, wherein said disorder isa disorder selected from the following: (i) psychosis in a patientsuffering from depression; (2) depression in a patient suffering frompsychosis; (3) mood disorders associated with psychosis; (4) sleepdisorders associated with psychosis; and (5) substance addiction,substance use disorders and/or substance-induced disorders.
 18. Themethod according to claim 14, wherein said disorder is a disorderselected from obsessive-compulsive disorder (OCD), obsessive-compulsivepersonality disorder (OCPD), general anxiety disorder, social anxietydisorder, panic disorder, agoraphobia, compulsive gambling disorder,compulsive eating disorder, body dysmorphic disorder, hypochondriasis,pathological grooming disorder, kleptomania, pyromania, attentiondeficit-hyperactivity disorder (ADHD), attention deficit disorder (ADD),impulse control disorder, and combination thereof.
 19. The methodaccording to claim 14, wherein said disorder is a disorder selected frompain, cephalic pain, idiopathic pain, neuropathic pain, chronic pain,fibromyalgia, chronic fatigue, opiate dependency, cocaine dependency,amphetamine dependency, alcohol dependency, withdrawal from drug oralcohol dependency, and opiate overdose.
 20. The method according toclaim 14, wherein the method further comprises administration of anagonist or partial agonist, or inverse agonist or antagonist, of themu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphaninreceptors.
 21. The method according to claim 14, wherein the methodfurther comprises administration of buprenorphine, methadone, naloxoneor naltrexone.
 22. The method according to claim 14, wherein the methodcomprises administering the compound of Formula I.
 23. The methodaccording to claim 22, wherein, in the compound of Formula I, Z is O.24. The method according to claim 22, wherein, in the compound ofFormula I, Z is —C(O).
 25. The method according to claim 22, wherein, inthe compound of Formula I, R⁵ is —C(O)—O—C(R^(a))(R^(b))(R^(c)).
 26. Themethod according to claim 22, wherein, in the compound of Formula I, R⁵is —C(O)—O—CH₂—O—C(R^(a))(R^(b))(R^(c)).
 27. The method according toclaim 22, wherein, in the compound of Formula I, R⁵ is—C(R⁶)(R⁷)—O—C(O)—R⁸, and R⁸ is —C(R^(a))(R^(b))(R^(c)).
 28. The methodaccording to claim 22, wherein, in the compound of Formula I, R⁵ is—C(R⁶)(R⁷)—O—C(O)—R⁸, and R⁸ is —O—C(R^(a))(R^(b))(R^(c)).
 29. Themethod according to claim 22, wherein, in the compound of Formula I, R⁵is —C(R⁶)(R⁷)—O—C(O)—R⁸, and R⁸ is —N(R^(d))(R^(e)).
 30. The methodaccording to claim 22, wherein the compound of Formula I is in the formof a pharmaceutically acceptable salt.
 31. The method according to claim14, wherein the method comprises administering the compound of FormulaII.
 32. The method according to claim 31, wherein the compound ofFormula II is in the form of a pharmaceutically acceptable salt.
 33. Themethod according to claim 14, wherein the method comprises administeringthe compound of Formula I or the compound of Formula II in the form of apharmaceutical composition comprising the compound of Formula I or thecompound of Formula II in free or pharmaceutically acceptable salt form,in admixture with a pharmaceutically acceptable diluent or carrier, andwherein the composition is formulated as a long acting injectable. 34.The method according to claim 33, wherein the long acting injectable isa subcutaneous or intramuscular injection.